Healthy Living Strategies

Abigail Enterprises 4 Healthy Living Strategies

Honoring the Memory of Sergut Araya Sellassie

by

Abigail Mariam Belai and Belai Mariam Habte-Jesus

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ASA Foundation- A living memory of the life and work of Sergut A Sellassie

 

A short life history of “Sergut Araya Selassie”

1956-2016

 

Mrs. Sergut Araya Selassie was born on May 6, 1956 (Miazia 28, 1948,E.C.) in the city of Harer from her parents (Father: Fitawrari Araya Selassie Zeleke and Mother: Mrs. Zelekawork Mengistu).

 

Sergut Araya Selassie completed her elementary and high school education at the Private Girls Education Center of “Nazareth School” in Addis Ababa. She later went to the United States to complete her higher college education at the University of San Francisco, California where she received her Bachelor of Arts Degree with honors. Sergut worked with a series of Public and Private Institutions in the West and East Coast of the United States with honor and distinction.

 

Sergut was married to Dr Belai Habte-Jesus on September 11, 1992 (Meskerem 2, 1985, E.C.,) in Washington DC, USA and became the mother of her only daughter Abigail Mariam Belai on 12 March 1994, at the Virginia Hospital Center, Arlington, Virginia. Sergut has worked with diligence and dignity in all her responsibilities and was able to raise and educate her daughter with love, respect, and discipline towards a responsible and talented youth that respects life, education and loves her family and her diverse international cultural communities.

 

In line with her noble family upbringing and Christian faith, Mrs. Sergut Araya Selassie has served her immediate family, friends and the larger communities with love, respect and compassion for which she has attained respect and admiration by all her families, friends and colleagues. She was specially admired and honored for character and special gift of respecting and honoring all her friends and associates.

 

Sergut passed away at the age of 60, on Monday 11 July 2016 at 00:00 a.m.4 (Monday, 04 Hamle 2008, E.C.) at the George Washington Hospital in Washington DC. USA. after a short illness and appropriate care by her beloved families, friends and Metropolitan Washington DC area hospitals and specialists. She died of Breast Cancer at the age of 60, when Breast Cancer the second most lethal cancer in women in the USA is usually diagnosed.

 

After a special prayer at the St. Michael Church, Washington DC on Thursday, 14 July 2016 (7 Hamle, 2008, E.C.,) at 10:00 am, her body will travel to Ethiopia accompanied by her beloved family on Friday 15 July 2016 and will be buried at Entoto, Hamere Noah Holy St Mary Monastery, Addis Ababa, Ethiopia on Saturday 16 July 2016 (09 Hamle 2008, E.C.,).

Psalms 23:

 

The Lord is my Shepherd, I shall not want. He makes me to lie down in green pastures; he leads me beside the still waters. He restoreth my soul: he leads me in the paths of righteousness for his name’s sake.

Yeah, though I walk through the valley of the shadow of death, I will fear no evil: for tough art with me; thy rod and thy staff they comfort me. Surely goodness and mercy shall follow me all the days of my life and I will dwell in the house of the Lord forever.

…With love and respect, From her beloved daughter Abigail Mariam Belai,Family and Friends around the world

 

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The Abigail Enterprises for Healthy Living

 

In honor of the memory Sergut A Selassie

 

SAS Foundation/Sergut Araya Selassie Foundation

 

Introduction

 

  • Abigail Belai and Belai Habte-Jesus are establishing “AE4HL/Abigail Enterprises 4 Healthy Living” in honor of Sergut A Sellassie (1956-2016)- The “SAS Foundation”, in memory of the beloved mother of Abigail Mariam Belai who lived a remarkable life of serving others in diversity to sustain our shred universal divinity with Marriott International in East and West Coast of the USA, IMF and World Bank institutions in the Metropolitan Washington DC area.

 

 

  1. Our Vision

 

  • To promote the culture of healthy living for sustainable development and progressive prosperity for all age diverse groups of populations around the world.

 

  1. Our Mission

 

  • To cultivate the culture of healthy living based on the latest scientific and cultural knowledge, evolving scientific discoveries to all communities.

 

  1. Our Goal

 

  • Our goal is to improve the KAP/knowledge, attitude and practice of all people (from conception to old age) towards promoting healthy and productive living in line with the latest scientific and cultural discovery and development respectively.

 

  1. Our SMART Work Plan

 

  • To establish and develop a sustainable public and private enterprise that promotes healthy living and productive life with all sectors of our communities via modern ICT/Information, Communication and Technology and SMN/Social Media Network.

 

 

  • Health Promotion and Disease Prevention Strategies

 

Defining Health Promotion and Disease Prevention

 

Health is positive sense of spiritual, emotional, psychological, mental, behavioral and physical well being. As such, Health is not a mere albescence of disease, injury, inflammation and disabilities. A positive sense of wellbeing is dependent on our positive interaction with integrated individual, group, personal and social relationships with the ecology we live in.

 

Health promotion and disease prevention programs focus on keeping people healthy.

 

Health promotion engages and empowers individuals and communities to engage in healthy behaviors, and make changes that reduce the risk of developing chronic diseases, injury, inflammation, disabilities and other morbidities.

 

 

 

As defined by the World Health Organization, health promotion is:

The process of enabling people to increase control over, and to improve, their health. It moves beyond a focus on individual behavior towards a wide range of social and environmental interventions.”

 

Disease prevention focuses on prevention strategies to reduce the risk of developing acute and chronic diseases, injuries, inflammation, disabilities and other morbidities.

 

Health promotion and disease prevention programs often address social determinants of health, which influence modifiable risk behaviors.

 

Social determinants of health are the economic, social, cultural, and political conditions in which people are born, grow, and live that affect health status. Modifiable risk behaviors include, for example, tobacco use, poor eating habits, and lack of physical activity, which contribute to the development of chronic disease.

 

SAS Foundation Projects and Activities

 

  1. Health Promotion: Choosing a healthy life style all the time!

Integrating restful sleep, balanced diet and leisurely activities

 

Typical activities for health promotion and disease prevention programs include:

  • 1 Interactive Communication: Raising awareness about healthy behaviors for the general public. Examples of communication strategies include public service announcements, health fairs, mass media campaigns, with classical and modern communication tools such as ICT/Information & Communication Technologies, SMN/Social Media Networks and newsletters.
  • 2Education: Empowering behavior change and actions through increased knowledge. Examples of education strategies include seminars, webinars, courses, trainings, and support groups.
  • 3 Policy: Working with public and private organizations to promote regulating or mandating activities by organizations or public agencies that encourage healthy decision-making.
  • 3 Environment: Changing structures or environments to make healthy decisions more readily available to large populations such as schools, churches, social networks, government institutions, etc.

1.4 Training Modules. Health promotion and disease prevention program models are provided in Modules.

 

 

Resources to Learn More

  1. Chronic Disease Prevention and Health PromotionWebsite
  2. Provides information, statistics, tools, and resources related to health promotion and disease prevention program planning.
  3. Organization(s): HHS, NIH, Centers for Disease Control and Prevention, WHO
  4. Milestones in Health Promotion: Statement from Global Conferences
  5. Publication: This publication provides information on the global definition of health promotion and various actions that can help support and improve health outcomes.
  6. Organization(s): World Health Organization
Date: 2009
  7. National Prevention Strategy: America’s Plan for Better Health and Wellness

Website

  1. The overarching goal of this website is to increase the number of Americans who are healthy at every stage of life. The strategy provides evidence-based recommendations through the active engagement of all sectors of society to help achieve four broad strategic directions.
  2. Organization(s): Centers for Disease Control and Prevention
  3. The Power of Prevention: Chronic Disease…the Public Health Challenge of the 21st Century
  4. Publication
  5. A publication covering chronic diseases, what causes them and at what cost. Also includes a vision for prevention and a call to action.
  • Common Preventable Conditions

ABC of Preventable diseases:

 

Headaches: Cluster and Migrain Headaches

 

U.S. National Library of Medicine

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Article

 

A cluster headache is a type of headache.

 

It is one-sided head pain that may involve tearing of the eyes, a droopy eyelid, and a stuffy nose.

 

Attacks occur regularly for 1 week to 1 year. The attacks are separated by pain-free periods that last at least 1 month or longer.

 

Cluster headaches may be confused with other common types of headaches such as migraines, sinus headache, and tension headache.

 

 

 

 

 

Allergic or Histamine or Serotonin Cluster Headaches

 

Causes

Doctors do not know exactly what causes cluster headaches.

 

They seem to be related to the body’s sudden release of histamine (chemical in the body released during an allergic response) or serotonin (chemical made by nerve cells).

 

A problem in a small area at the base of the brain called the hypothalamus may be involved.

 

More men than women are affected.

 

The headaches can occur at any age, but are most common in the 20s through middle age.

 

They tend to run in families.

Cluster headaches may be triggered by:

Alcohol and cigarette smoking

High altitudes (trekking and air travel)

Bright light (including sunlight)

Exertion (physical activity)

Heat (hot weather or hot baths)

Foods high in nitrites (bacon and preserved meats)

Certain medicines

Cocaine

Symptoms

A cluster headache begins as a severe, sudden headache. The headache commonly strikes 2 to 3 hours after you fall asleep. But it can also occur when you are awake. The headache tends to happen daily at the same time of day. Attacks can last for months. They can alternate with periods without headaches (episodic) or they can go on for a year or more without stopping (chronic).

Cluster headache pain is usually:

Burning, sharp, stabbing, or steady

Felt on one side of the face from neck to temple, often involving the eye

At its worst within 5 to 10 minutes, with the strongest pain lasting 30 minutes to 2 hours

When the eye and nose on the same side as the head pain are affected, symptoms can include:

Swelling under or around the eye (may affect both eyes)

Excessive tearing

Red eye

Droopy eyelid

Runny nose or stuffy nose on the same side as the head pain

Red, flushed face, with extreme sweating

Exams and Tests

Your health care provider can diagnose this type of headache by performing a physical exam and asking about your symptoms and medical history.

If a physical exam is done during an attack, the exam will usually reveal Horner syndrome (one-sided eyelid drooping or a small pupil). These symptoms will not be present at other times. No other nervous system (neurologic) changes will be seen.

Tests, such as an MRI of the head, may be needed to rule out other causes of the headaches.

Treatment

Treatment for cluster headaches involves:

Medicines to treat the pain when it happens

Medicines to prevent the headaches

TREATING CLUSTER HEADACHES WHEN THEY OCCUR

Your provider may recommend the following treatments for when the headaches occur:

Triptan medicines, such as sumatriptan (Imitrex).

Anti-inflammatory (steroid) medicines such as prednisone. Starting with a high dose, then slowly decreasing it over 2 to 3 weeks.

Breathing in 100% (pure) oxygen.

Injections of dihydroergotamine (DHE), which can stop cluster attacks within 5 minutes (Warning: this drug can be dangerous if taken with sumatriptan).

You may need more than one of these treatments to control your headache.

 

Your provider may have you try several medicines before deciding which works best for you.

 

Pain medicines and narcotics do not usually relieve cluster headache pain, because they take too long to work.

 

Surgical treatment may be recommended for you when all other treatments have failed. One such treatment is a neurostimulator. This device delivers tiny electrical signals to a certain nerve near the brain. Your provider can tell you more about surgery.

 

PREVENTING CLUSTER HEADACHES

Avoid smoking, alcohol use, certain foods, and other things that trigger your headaches. A headache diary can help you identify your headache triggers. When you get a headache, write down the following:

Day and time the pain began

What you ate and drank over the past 24 hours

How much you slept

 

What you were doing and where you were right before the pain started

 

How long the headache lasted and what made it stop

Review your diary with your provider to identify triggers or a pattern to your headaches. This can help you and your provider create a treatment plan. Knowing your triggers can help you avoid them.

 

The headaches may go away on their own or you may need treatment to prevent them.

 

The following medicines may also be used to treat or prevent headache symptoms:

 

Allergy medicines

Antidepressants

Blood pressure medicines

Seizure medicine

 

Outlook (Prognosis)

Cluster headaches are not life threatening. They usually do not cause permanent changes to the brain. But they are chronic, and often painful enough to interfere with work and life.

 

When to Contact a Medical Professional

 

 

 

 

 

Call 911 if:

You are experiencing “the worst headache of your life.”

You have speech, vision, or movement problems or loss of balance, especially if you have not had these symptoms with a headache before.

 

A headache starts suddenly.

Schedule an appointment or call your provider if:

Your headache pattern or pain changes.

Treatments that once worked no longer help.

You have side effects from your medicine.

You are pregnant or could become pregnant. Some medicines should not be taken during pregnancy.

You need to take pain medicines more than 3 days a week.

Your headaches are more severe when lying down.

 

Prevention

If you smoke, now is a good time to stop. Alcohol use and any foods that trigger a cluster headache may need to be avoided. Medicines may prevent cluster headaches in some cases.

 

Alternative Names

Histamine headache; Headache – histamine; Migrainous neuralgia; Headache – cluster; Horton’s headache; Vascular headache – cluster 

 

References

Ferri FF. Cluster headache. In: Ferri FF, ed. Ferri’s Clinical Advisor 2016. Philadelphia: PA: Elsevier Saunders; 2016:347.

Petersen AS, Barloese MC, Jensen RH. Oxygen treatment of cluster headache: a review. Cephalalgia. 2014;34:1079-1087. PMID: 24723673 www.ncbi.nlm.nih.gov/pubmed/24723673.

Silberstein SD. Headache management. In: Benzon HT, Rathmell JP, Wu CL, Turk DC, Argoff CE, Hurley RW, eds. Practical Management of Pain. 5th ed. Philadelphia, PA: Elsevier Mosby; 2014:chap 30.

Weaver-Agostoni J. Cluster headache. Am Fam Physician. 2013;88:122-128. PMID: 23939643 www.ncbi.nlm.nih.gov/pubmed/23939643.

 

 

Update Date 1/5/2016

Updated by: Joseph V. Campellone, MD, Division of Neurology, Cooper University Hospital, Camden, NJ. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team.

 

Browse the Encyclopedia

Related MedlinePlus Health Topics

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Migraine

Serotonin blood test

Patient Instructions

Headache – what to ask your doctor

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Page last updated: 23 August 2016

 

 

 

 

 

 

 

 

Cancer is unlimited growth of abnormal cells in the body due to failure of the normal control mechanisms of the body.

 

Carcinogenesis is the process in which normal cells turn into cancer cells.

 

  • Carcinogenesis is the series of steps that take place as a normal cell becomes a cancer Cells are the smallest units of the body and they make up the body’s tissues.

 

  • Each cell contains genes that guide the way the body grows, develops, and repairs itself.

 

 

  • There are many genes that control whether a cell lives or dies, divides (multiplies), or takes on special functions, such as becoming a nerve cell or a muscle cell.

 

Changes (mutations) in genes occur during carcinogenesis.

 

Changes (mutations) in genes can cause normal controls in cells to break down. When this happens, cells do not die when they should and new cells are produced when the body does not need them. The buildup of extra cells may cause a mass (tumor) to form.

 

Normal Cell

 

In biology, the smallest unit that can live on its own and that makes up all living organisms and the tissues of the body.

 

A cell has three main parts: the cell membrane, the nucleus, and the cytoplasm. The cell membrane surrounds the cell and controls the substances that go into and out of the cell.

 

The nucleus is a structure inside the cell that contains the nucleolus and most of the cell’s DNA. It is also where most RNA is made.

 

The cytoplasm is the fluid inside the cell. It contains other tiny cell parts that have specific functions, including the Golgi complex, the mitochondria, and the endoplasmic reticulum.

 

The cytoplasm is where most chemical reactions take place and most proteins get made.

 

The human body has more than 30 trillion cells.

ENLARGE

 

 

 

 

The stem cell microenvironment is involved in regulating the fate of the stem cell with respect to self-renewal, quiescence, and differentiation.

 

Mathematical models are helpful in understanding how key pathways regulate the dynamics of stem cell maintenance and homeostasis.

 

This tight regulation and maintenance of stem cell number is thought to break down during carcinogenesis. As a result, the stem cell niche has become a novel target of cancer therapeutics.

 

Developing a quantitative understanding of the regulatory pathways that guide stem cell behavior will be vital to understanding how these systems change under conditions of stress, inflammation, and cancer initiation. Predictions from mathematical modeling can be used as a clinical tool to guide therapy design.

 

 

 

Tumors can be benign or malignant (cancerous). Malignant tumor cells invade nearby tissues and spread to other parts of the body. Benign tumor cells do not invade nearby tissues or spread.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  • Cancer Prevention Strategies

 

Strategies: How to prevent cancer

  1. Understand the enemy, that is cancer
  2. Know the causes of cancer
  3. Identify your risks of cancer
  4. Change your life style
  5. Reduce your risks
  6. Eliminate your threats
  7. Change your challenges into opportunities

 

Cancer is the uncontrolled growth of abnormal cells in the body. Cancer develops when the body’s normal control mechanism stops working. Normal cells grow old and are replaced by new cells.

 

Old cells do not die and cells grow out of control, forming new, abnormal cells. These extra cells may form a mass of tissue, called a tumor. Some cancers, such as leukemia, do not form tumors.

 

What are the most common forms of cancer?

 

Cancer can occur anywhere in the body. In women, breast cancer is most common. In men, it’s prostate cancer. Lung cancer and colorectal cancer affect both men and women in high numbers.

 

There are five main categories of cancer:

1.Carcinomas begin in the skin or tissues that line the internal organs.

2.Sarcomas develop in the bone, cartilage, fat, muscle or other connective tissues.

3.Leukemia begins in the blood and bone marrow.

4.Lymphomas start in the immune system.

5.Central nervous system cancers develop in the brain and spinal cord.

 

When you hear the word “cancer,” what comes to mind?

 

Is it the fear of ever being diagnosed? Or of watching the person closest to you get the news? Maybe it’s the triumphant feeling of having battled the disease until it’s finally in remission.

 

Many people associate cancer with the emotions it evokes: the shock, the sadness, the bravery and the exhilaration. Why cancer develops and why it responds to certain treatments is more of a mystery.

 

About 13 million Americans have cancer and more than 1 million are diagnosed every year.

 

To shed light on the disease, CTCA /Cancer Treatment Center of America, developed The Anatomy of Cancer, a five-minute video that explains cancer in everyday terms. The goal of the video is to answer the key questions so many people have about cancer.

 

What is cancer?

Cancer is the uncontrolled growth of abnormal cells in the body. In the body, there are trillions of cells with various functions. These cells grow and divide to help the body function properly. Cells die when they become old or damaged, and new cells replace them.

 

Cancer develops when the body’s normal control mechanism stops working. Old cells do not die and cells grow out of control, forming new, abnormal cells. These extra cells may form a mass of tissue, called a tumor. Some cancers, such as leukemia, do not form tumors.

 

There are five main categories of cancer:

  1. Carcinomas begin in the skin or tissues that line the internal organs.
  2. Sarcomas develop in the bone, cartilage, fat, muscle or other connective tissues.
  3. Leukemia begins in the blood and bone marrow.
  4. Lymphomas start in the immune system.
  5. Central nervous system cancers develop in the brain and spinal cord.

 

Cancer can occur anywhere in the body. In women, breast cancer is most common. In men, it’s prostate cancer. Lung cancer and colorectal cancer affect both men and women in high numbers

 

How is cancer treated?

The same cancer type—whether it’s liver cancer, stomach cancer or kidney cancer—in one individual is very different from that cancer in another individual.

 

In fact, cancer is not one disease but hundreds of different types of diseases. Within a single type of cancer, such as breast cancer, researchers are discovering subtypes that each requires a different treatment approach.

 

Treatment options depend on the type of cancer, its stage, if the cancer has spread and your general health.

 

The three main treatments are:

1.Surgery: directly removing the tumor

2.Chemotherapy: using chemicals to kill cancer cells

  1. Radiation therapy: using X-rays to kill cancer cells

 

The goal of treatment is to kill as many cancerous cells while minimizing damage to normal cells nearby.

 

Advances in technology make this possible. For example, intraoperative radiation therapy (IORT) delivers a concentrated dose of radiation to a tumor site immediately after surgery. Healthy tissues and organs are shielded during treatment, which allows for a higher dose of radiation.

 

In recent years, doctors have been able to offer treatment options based on the genetic changes occurring in a specific tumor. An innovative new diagnostic tool, the genomic tumor assessment, examines a patient’s tumor genetically to help identify mechanisms that may be responsible for the cancer’s growth.

 

Genomic tumor assessment can result in a more personalized approach to cancer treatment.

 

Learn about our approach to treating cancer.

How to eat for hormonal balance: Nutrition tips for every woman

Faith offers optimism and inner strength during cancer treatment

 

How is cancer treated?

 

Treatment options depend on the type of cancer, its stage, if the cancer has spread and your general health. The goal of treatment is to kill as many cancerous cells while minimizing damage to normal cells nearby. Advances in technology make this possible.

 

The three main treatments are:

  1. Surgery: directly removing the tumor
  2. Chemotherapy: using chemicals to kill cancer cells
  3. Radiation therapy: using X-rays to kill cancer cells

 

The same cancer type in one individual is very different from that cancer in another individual. Within a single type of cancer, such as breast cancer, researchers are discovering subtypes that each requires a different treatment approach.

 

What can you do to manage the side effects of cancer treatment?

 

Integrative oncology services describe a broad range of complementary treatments that combat side effects, boost the immune system and maintain well-being.

 

Treating cancer cannot focus on the disease alone but must address the pain, fatigue and depression that comes with it.

 

Integrative oncology services include:

  1. Nutrition therapy to help prevent malnutrition and reduce side effects
  • Naturopathic medicine to safely strengthen your immune system, boost your energy and reduce side effects
  • Oncology rehabilitation to rebuild strength and overcome some of the physical effects of treatment
  • Mind-body medicine to improve emotional well-being through counseling, stress management techniques and support groups

What does the future hold for cancer treatment?

The future of cancer treatment lies in providing patients with an even greater level of personalization.

 

Doctors are beginning to offer treatment options based on the genetic changes occurring in a specific tumor.

 

An innovative new diagnostic tool, the genomic tumor assessment, examines a patient’s tumor genetically to identify the mechanism that caused the cancer. Genomic tumor assessment can result in a more personalized approach to cancer treatment.

 

 

1.What is nutrition therapy?

Many cancer patients experience gastrointestinal symptoms. The Nutrition Therapy team helps restore digestive health, prevent malnutrition and provide dietary recommendations during treatment. Our goal is to help you stay strong and nourished, so you can continue with your cancer treatment.

 

Every patient is scheduled to meet with a registered dietitian during the first visit to CTCA. During this visit, you are given a full assessment to identify daily goals for calories and protein. Your dietitian will look at your health history, disease type and treatment plan to recommend nourishing foods during your cancer care.

 

Your dietitian will monitor your nutrition status from the beginning to the end of your cancer treatment, making modifications as needed to minimize side effects and treatment interruptions before they arise.

 

Your dietitian communicates regularly with your oncologists and the other members of your cancer team. Working together in close proximity allows for a fully integrated approach to treating cancer. Your dietitian is able to share any specific nutrition challenges with other members of your care team, such as your oncologist. Everyone works together to find solutions that meet your individual needs.

 

We also provide information and classes about healthy eating habits to your caregivers and family members, so you can continue a healthy lifestyle at home.

 

  1. What is naturopathic medicine?

Naturopathic medicine is an approach to health care that uses natural, non-toxic therapies to treat the whole person and encourage the self-healing process. Naturopathic clinicians treat a variety of conditions, including digestive issues, respiratory conditions, chronic fatigue syndrome and cancer.

 

As part of our integrative oncology services, our naturopathic oncology providers focus on reducing the risk of harmful effects from cancer treatments. With a wide variety of natural therapies available, they select and propose the intervention that is appropriate for your health. Your naturopathic oncology provider acts as a consultant to your oncologist to support normal metabolism and digestion during cancer treatment; manage any side effects, such as nausea or fatigue; and boost immune function.

 

As part of the intake process, you’ll meet with your naturopathic oncology provider, who will review your history and make recommendations from a wide variety of natural therapies.

 

Your naturopathic oncology provider also will review current supplements to identify herb-drug-nutrient interactions.

 

Throughout your treatment, your naturopathic oncology provider will recommend natural therapies to support your immune system and reduce any treatment-related side effects, including:

 

  1. Herbal and botanical preparations, including herbal extracts and teas.
  2. Dietary supplements, including vitamins, minerals and amino acids.
  3. Homeopathic remedies, extremely low doses of plant extracts and minerals that gently strengthen the body’s healing and immune response.
  4. Physical therapy and exercise therapy, including massage and other gentle techniques used on deep muscles and joints for therapeutic purposes.
  5. Hydrotherapy, which prescribes water-based approaches like hot and cold wraps, and other therapies.
  6. Lifestyle counseling: Many medical conditions can be treated with exercise, improved sleep, stress reduction techniques, as well as foods and nutritional supplements.
  7. Acupuncture: Your naturopathic oncology provider may also recommend incorporating acupuncture into your treatment plan.
  8. Chiropractic care, which may include hands-on adjustment, massage, stretching, electronic muscle stimulation, traction, heat, ice and other techniques to alleviate pain, headaches, nausea, peripheral neuropathy and stiffness or weakness in the muscles and joints.

 

 

Experienced care team

  • All of our naturopathic oncology providers have extensive knowledge of radiation therapy, chemotherapy and other cancer treatments, in addition to their expertise in the effects of natural therapies. As a part of your care team, they are in regular communication with your oncologists and other clinicians to help guide your treatment plan.

 

Personalized treatment approach

  • We personalize treatment plans to the individual based on each person’s goals and experiences. Your care team would help you decide which naturopathic medicine therapies would help achieve your goals. You may have one or more of the above therapies during the course of your treatment.

 

 

  1. What is mind-body medicine?

The Mind-Body Medicine Program at Cancer Treatment Centers of America (CTCA) supports you and your caregivers before, during and after cancer treatment.

 

Mind-body medicine, an integral part of whole-person care, recognizes the powerful ways in which emotional, mental, social and behavioral factors can directly affect health.

 

Licensed mental health and allied professionals offer caring relationships and therapeutic practices and techniques to help you and your caregivers respond to cancer diagnosis and treatment in empowering and stress-minimizing ways in order to improve your health, relationships and overall well-being.

 

Mind-body services

All of mind-body services are available to patients and caregivers. Each new patient is scheduled to meet with a mind-body therapist at least once to introduce the services. It’s your decision if you would like to continue meeting with a mind-body therapist and/or participate in any of the following services:

 

Individual, couples and family counseling: Meet with your mind-body therapist as an individual, couple or family for help with anything on your mind, work through difficult decisions, cope with cancer and how it affects your life and relationships, discover and use your inner strengths and resources, and explore ways to enjoy life while on this journey.

 

Relaxation and guided imagery: Learn to use positive mental images and focused breathing to increase your physical and emotional comfort. Cancer patients have often found this to help with physical discomfort and stress. It can also help support the immune system.

 

Support groups: Connect with others going through a similar experience.

 

Wellness practices for stress management/reduction: Discover tools and strategies that you can build into your everyday life to help reduce stress and positively affect your well-being.

Therapeutic laughter: Enjoy a distraction from your everyday stresses by joining in laughter exercises. Research has shown that positive laughter and humor can offer many physical and psychological health benefits.

 

Mind-body therapists work closely with your entire cancer treatment team and are here to support you in making ongoing care decisions. In addition, they can try to connect you with qualified practitioners, support groups and counseling services in your area once you return home.

 

 

When you hear the word “cancer,” what comes to mind?

Is it the fear of ever being diagnosed? Or of watching the person closest to you get the news? Maybe it’s the triumphant feeling of having battled the disease until it’s finally in remission.

 

Many people associate cancer with the emotions it evokes: the shock, the sadness, the bravery and the exhilaration. Why cancer develops and why it responds to certain treatments is more of a mystery.

 

  • About 13 million Americans have cancer and more than 1 million are diagnosed every year.

 

To shed light on the disease, CTCA developed The Anatomy of Cancer, a five-minute video that explains cancer in everyday terms. The goal of the video is to answer the key questions so many people have about cancer.

 

What is cancer?

  • Cancer is the uncontrolled growth of abnormal cells in the body. In the body, there are trillions of cells with various functions. These cells grow and divide to help the body function properly. Cells die when they become old or damaged, and new cells replace them.

 

  • Cancer develops when the body’s normal control mechanism stops working. Old cells do not die and cells grow out of control, forming new, abnormal cells. These extra cells may form a mass of tissue, called a tumor. Some cancers, such as leukemia, do not form tumors.

 

There are five main categories of cancer:

  1. Carcinomas begin in the skin or tissues that line the internal organs.
  2. Sarcomas develop in the bone, cartilage, fat, muscle or other connective tissues.
  3. Leukemia begins in the blood and bone marrow.
  4. Lymphomas start in the immune system.
  5. Central nervous system cancers develop in the brain and spinal cord.

 

Cancer can occur anywhere in the body. In women, breast cancer is most common. In men, it’s prostate cancer. Lung cancer and colorectal cancer affect both men and women in high numbers.

 

How is cancer treated?

 

  • In fact, cancer is not one disease but hundreds of different types of diseases. Within a single type of cancer, such as breast cancer, researchers are discovering subtypes that each requires a different treatment approach.

 

  • Treatment options depend on the type of cancer, its stage, if the cancer has spread and your general health. The three main treatments are:
  1. Surgery: directly removing the tumor
  2. Chemotherapy: using chemicals to kill cancer cells
  3. Radiation therapy: using X-rays to kill cancer cells

 

The goal of treatment is to kill as many cancerous cells while minimizing damage to normal cells nearby. Advances in technology make this possible. For example, intraoperative radiation therapy (IORT) delivers a concentrated dose of radiation to a tumor site immediately after surgery.

 

Healthy tissues and organs are shielded during treatment, which allows for a higher dose of radiation.

 

In recent years, doctors have been able to offer treatment options based on the genetic changes occurring in a specific tumor. An innovative new diagnostic tool, the genomic tumor assessment, examines a patient’s tumor genetically to help identify mechanisms that may be responsible for the cancer’s growth.

 

Genomic tumor assessment can result in a more personalized approach to cancer treatment.

Learn about our approach to treating cancer.

How to eat for hormonal balance: Nutrition tips for every woman

Faith offers optimism and inner strength during cancer treatment

 

 

Intraoperative radiation therapy

What is it?

InIN

TRABEAM IORT

What is IORT?

·       Intraoperative radiation therapy (IORT) delivers a concentrated dose of radiation therapy to a tumor

·       bed during surgery. This advanced technology may help kill microscopic disease, reduce radiation

·       treatment times or provide an added radiation “boost.”

Advantages of IORT

·       Typically, standard radiation therapy involves five days of treatment per week, for a total of five to six

·       weeks for some patients.

·       With IORT, our radiation oncologists can deliver a similar dose of radiation in a single treatment session,

·       while also preserving more healthy tissue. This helps to reduce side effects and the time spent going back

·       and forth to the hospital for radiation treatments.

 

IORT offers some of the following advantages:

Maximum effect. IORT delivers a concentrated dose of radiation to a tumor site immediately after

a tumor is removed, helping to destroy the microscopic tumor cells that may be left behind.

The tumor site is typically at high risk for recurrence and traditional radiation therapy requires a recovery

period after surgery, which leaves microscopic disease in the body for longer.

Spares healthy tissues and organs. During IORT, a precise radiation dose is applied while shielding

healthy tissues or structures, such as the skin, that could be damaged using other techniques. This allows a

higher radiation dose to be delivered to the tumor bed, while sparing normal surrounding tissues. Critical

organs within the radiation field, such as the lungs or heart, can also be protected.

 

Shortened treatment times. IORT may help some patients finish treatment and get back to their lives

quicker by reducing the need for additional radiation therapy, which is typically given over five to six weeks.

The IORT treatment itself takes about four to five minutes.

 

A “boost” for traditional radiation patients. Patients who must receive additional radiation therapy

following surgery can receive a boost of radiation during IORT. After they have recovered from

the surgical procedure, they can continue with their radiation treatments, with typically fewer

complications.

A patient must be a surgical candidate in order to be eligible for IORT. This treatment is generally

reserved for individuals with early-stage disease.

 

 

 

Breast Cancer

 

Breast cancer is a group of diseases that affects breast tissue. Both women and men can get breast cancer, though it is much more common in women. Other than skin cancer, breast cancer is the most common cancer among women in the United States. Some women are at higher risk for breast cancer than others because of their personal or family medical history or because of certain changes in their genes.

 

Getting mammograms regularly can lower the risk of dying from breast cancer. The United States Preventive Services Task Force recommends that average-risk women who are 50 to 74 years old should have a screening mammogram every two years. Average-risk women who are 40 to 49 years old should talk to their doctor about when to start and how often to get a screening mammogram.

Most health insurance programs cover mammograms. You can get a screening mammogram without any out-of-pocket costs. If you are worried about the cost or don’t have health insurance, CDC offers free or low-cost mammograms and education about breast cancer.

 

 

Cancer is a disease in which cells in the body grow out of control. Except for skin cancer, breast cancer is the most common cancer in women in the United States. Deaths from breast cancer have declined over time, but remains the second leading cause of cancer death among women overall and the leading cause of cancer death among Hispanic women.

 

Each year in the United States, about 220,000 cases of breast cancer are diagnosed in women and about 2,000 in men. About 40,000 women and 400 men in the U.S. die each year from breast cancer.

 

Over the last decade, the risk of getting breast cancer has not changed for women overall, but the risk has increased for black women and Asian and Pacific Islander women. Black women have a higher risk of death from breast cancer than white women.

 

The risk of getting breast cancer goes up with age. In the United States, the average age when women are diagnosed with breast cancer is 61. Men who get breast cancer are diagnosed usually between 60 and 70 years old.

 

 

 

Cancer Prevention During Midlife

 

CDC’s Division of Cancer Prevention and Control sponsored a supplemental issue of the American Journal of Preventive Medicine about ways to reduce cancer risk during midlife. The authors are experts from many different professions, showing the importance of working together to find effective ways to prevent cancer.

 

Midlife, the time roughly between 45 and 64 years of age, is when the effects of harmful exposures and health behaviors often start to appear.

 

At this age, adults may experience the onset of chronic diseases or other health problems. During this time of unique life transitions and health challenges, adults can make positive changes to reduce their cancer risk and support health during midlife and beyond.

 

Healthy behaviors for healthy living

 

Examples include—

  • Promoting behaviors that are generally healthy may lower individual cancer risk.
  • Getting enough physical activity. 30 to 60 minutes physical activities per day
  • Maintaining a healthy weight. Maintaining a Body Mass Index: 19-25 (wt/htxht)
  • Getting enough Sleeping 7-8 hours per day
  • Seeking appropriate medical care—
  • Blood sugar. Managing chronic diseases such as Maintaining BS (70-100)
  • Inflammation. Testing for hepatitis C virus (HCV) infection. Negative
  • Substance abuse: Alcohol, Drug and Tobacco. Getting help to quit smoking. No smoking
    • Screening for and managing

Screening for certain types of cancer.

 

Cancer Screening Tests

 

  • Screening means checking your body for cancer before you have symptoms. Getting screening tests regularly may find breast, cervical, and colorectal (colon) cancers early, when treatment is likely to work best. Lung cancer screening is recommended for some people who are at high risk.

 

Screening for Breast, Cervical, Colorectal (Colon), and Lung Cancers

CDC supports screening for breast, cervical, colorectal (colon), and lung cancers as recommended by the U.S. Preventive Services Task Force.

Breast Cancer

Mammograms are the best way to find breast cancer early, when it is easier to treat. For more information, visit Breast Cancer: What Screening Tests Are There?

Cervical Cancer

 

Colorectal (Colon) Cancer

  • Colorectal cancer almost always develops from precancerous polyps (abnormal growths) in the colon or rectum. Screening tests can find precancerous polyps, so they can be removed before they turn into cancer. Screening tests also can find colorectal cancer early, when treatment works best. For more information, visit Colorectal Cancer: What Should I Know About Screening?

Lung Cancer

  • The U.S. Preventive Services Task Force recommends yearly lung cancer screening with low-dose computed tomography (LDCT) for people who have a history of heavy smoking, and smoke now or have quit within the past 15 years, and are between 55 and 80 years old. For more information, visit Lung Cancer: What Screening Tests Are There?

 

Screening for Ovarian, Prostate, and Skin Cancers

  • Screening for ovarian, prostate, and skin cancers has not been shown to reduce deaths from those cancers.

Ovarian Cancer

Prostate Cancer

Skin Cancer

The U.S. Preventive Services Task Force has concluded that there is not enough evidence to recommend for or against routine screening (total-body examination by a clinician) to find skin cancers early. This recommendation is for people who do not have a history of skin cancer and who do not have any suspicious moles or other spots. For more information,

 

Skin Cancer: What Screening Tests Are There?

 

Articles in Supplement

Background: Midlife as a Critical Period for Prevention

  1. Ory MG, Anderson LA, Friedman DB, Pulczinski JC, Eugene N, Satariano WA. Cancer prevention among adults aged 45–64: Setting the stage. American Journal of Preventive Medicine 2014;46(3S1):S1–S6.
  2. White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Henley SJ. Age and cancer risk: a potentially modifiable relationship. American Journal of Preventive Medicine 2014;46(3S1):S7–S15.
  3. Cancer Risk and Protective Factors During Midlife
  4. Scoccianti C, Lauby-Secretan B, Bello PY, Chajes V, Romieu I. Female breast cancer and alcohol consumption: A review of the literature. American Journal of Preventive Medicine 2014;46(3S1):S16–S25.
  5. Gapstur SM, Diver WR, Stevens VL, Carter BD, Teras LR, Jacobs EJ. Work schedule, sleep duration, insomnia, and risk of fatal prostate cancer. American Journal of Preventive Medicine 2014;46(3S1):S26–S33.
  6. Carter BD, Diver WR, Hildebrand JS, Patel AV, Gapstur SM. Circadian disruption and fatal ovarian cancer. American Journal of Preventive Medicine 2014;46(3S1):S34–S41.
  7. Nelson CC, Wagner GR, Caban-Martinez AJ, Buxton OM, Kenwood CT, Sabbath EL, Hashimoto DM, Hopcia K, Allen J, Sorensen G. Physical activity and body mass index: the contribution of age and workplace characteristics. American Journal of Preventive Medicine 2014;46(3S1):S42–S51.
  8. Amadou A, Mejia GT, Fagherazzi G, Ortega C, Angeles-Llerenas A, Chajes V, Biessy C, Sighoko D, Hainaut P, Romieu I. Anthropometry, silhouette trajectory, and risk of breast cancer in Mexican women. American Journal of Preventive Medicine 2014;46(3S1):S52–S64.
  9. Keum N, Giovannucci EL. Folic acid fortification and colorectal cancer risk. American Journal of Preventive Medicine 2014;46(3S1):S65–S72.
  10. Taking Public Health Action to Prevent Cancer
  11. Holman DM, Grossman M, Henley SJ, Peipins LA, Tison L, White MC. Opportunities for cancer prevention during midlife: highlights from a meeting of experts. American Journal of Preventive Medicine 2014;46(3S1):S73–S80.
  12. Dacus HLM, O’Sullivan GM, Major A, White DE. The role of a state health agency in promoting cancer prevention at the community level: Examples from New York State. American Journal of Preventive Medicine 2014;46(3S1):S81–S86.
  13. Zonderman AB, Ejiogu N, Norbeck J, Evans MK. The influence of health disparities on targeting cancer prevention efforts. American Journal of Preventive Medicine 2014;46(3S1):S87–S97.
  14. Muirhead L. Cancer risk factors among persons with serious mental illness. American Journal of Preventive Medicine 2014;46(3S1):S98–S103.

Conclusion

  1. Gehlert S. Forging an integrated agenda for primary cancer prevention during midlife. American Journal of Preventive Medicine 2014;46(3S1):S104–S109.

 

  1. Kinds of Cancer
  2. How to Prevent Cancer or Find It Early
  3. Data and Statistics
  4. Research
  5. Promoting Cancer Prevention
    1. Reducing Excessive Alcohol Use
    2. Reducing Indoor Tanning Among Minors
    3. How to Reduce Radon in Homes
    4. Guide to Promoting Cancer Prevention in Your Community

 

 

Kinds of Cancer

CDC provides basic information and statistics about some of the most common cancers in the United States.

  • Bladder cancer risk factors include smoking, genetic mutations, and exposure to certain chemicals.
  • Breast cancer is the most common cancer among American women. Getting mammograms regularly can lower the risk of dying from breast cancer. Talk to your doctor about when to start and how often to get a screening mammogram.
  • Cervical cancer is highly preventable in most Western countries because screening tests and a vaccine to prevent human papillomavirus (HPV) infections, which cause most cervical cancers, are available.
  • Of cancers affecting both men and women, colorectal cancer (cancer of the colon and rectum) is the second leading cancer killer in the United States, but it doesn’t have to be. If you are 50 years old or older, get screened now.
  • Smoking is the most important risk factor for kidney and renal pelvis cancers. To lower your risk, don’t smoke, or quit if you do. Be very careful if you work with the chemical trichloroethylene.
  • To lower your risk for liver cancer, get vaccinated against Hepatitis B, get tested for Hepatitis C, and avoid drinking too much alcohol.
  • Lung cancer is the leading cause of cancer death and the second most common cancer among both men and women in the United States. The most important thing you can do to lower your lung cancer risk is to quit smoking and avoid secondhand smoke.
  • Ovarian cancer causes more deaths than any other cancer of the female reproductive system. But when ovarian cancer is found in its early stages, treatment works best.
  • Prostate cancer is the most common cancer among American men. Most prostate cancers grow slowly, and don’t cause any health problems in men who have them. Learn more and talk to your doctor before you decide to get tested or treated for prostate cancer.
  • Skin cancer is the most common cancer in the United States. Most cases of melanoma, the deadliest kind of skin cancer, are caused by exposure to ultraviolet (UV) light. To lower your skin cancer risk, protect your skin from the sun and avoid indoor tanning.
  • Uterine cancer is the fourth most common cancer in women in the United States and the most commonly diagnosed gynecologic cancer.

Vaginal and vulvar cancers are rare, but all women are at risk for these cancers.

 

 

Prevention is the best way to fight cancer.

 

Policymakers, public health professionals, comprehensive cancer control programs, community groups, doctors, and individuals can help prevent cancer in many ways.

 

 

The Road to Better Health: A Guide to Promoting Cancer Prevention in Your Community

 

This tool kit helps community groups—

  • Educate people on how cancer affects your community.
  • Give people tips on how to lower their cancer risk.
  • Work with other groups and community leaders to make sure people have the information and services they need.
  • Become known as a community leader in the fight against cancer.
  • Use CDC’s tools and materials to spread the word.

 

 

Policies and Practices for Cancer Prevention:

Indoor Tanning Among Minors

 

Indoor Tanning Among Minors Promising Practices Brief[PDF-1.7MB]

 

  • Skin cancer is the most common form of cancer in the United States and has been identified by the Surgeon General as a serious public health problem.

 

  • The most common types of skin cancer—basal and squamous cell carcinoma—are usually treatable but can be disfiguring and expensive to treat.

 

1 Melanoma is a less common but deadly form of skin cancer.

2 Most skin cases of cancer are caused, in part, by exposure to ultraviolet (UV) radiation from the sun or from indoor tanning.

 

Limited UV exposure from the sun can have benefits such as improving a person’s mood and stimulating the body’s production of vitamin D.

 

Excessive UV exposure from indoor tanning and sunbathing offers no additional health benefits and increases the risk of harms from UV exposure.36

 

Indoor tanning in particular may expose users to excessive levels of UV radiation, which are not only harmful but also easily avoidable.7, 8 This excessive UV exposure greatly increases a person’s risk of getting melanoma, as well as basal and squamous cell carcinomas.912

 

 

Estimates from a recent study indicate that each year in the United States, more than 400,000 new cases of skin cancer (245,000 basal cell carcinomas, 168,000 squamous cell carcinomas, and 6,000 melanomas) may be related to indoor tanning.13

 

Indoor tanners are also at increased risk for other adverse effects of excessive UV exposure, including damage to the immune system, premature skin aging, and eye diseases such as cataracts, macular degeneration, and certain eye cancers.1417

 

The public health community plays an important role in educating young people about protecting themselves from the harms of indoor tanning. Many public health efforts focus on educational and messaging strategies.

 

Other efforts focus on providing the scientific evidence that can inform policy approaches, including regulatory or legislative strategies, to reduce indoor tanning among minors.

 

Some of these strategies are happening at the national level, such as regulating tanning devices by the U.S. Food and Drug Administration.18 Most are happening within individual states and local communities and often include restrictions on minors’ access to indoor tanning such as age restrictions, parental consent laws, and parental accompaniment laws.1921

 

Outside the United States, many countries have banned indoor tanning for individuals younger than age 18 years in an effort to prevent skin cancer.21, 22 By incorporating the scientific evidence and lessons learned from local, state, national, and international public health communities, we can coordinate our efforts and best use our resources to protect the future health of today’s youth.

 

Policies and Practices for Cancer Prevention

 

Reducing Excessive Alcohol Use

Alcohol use increases the risk of several cancers. This publication provides information about alcohol use among young people and adults and potential strategies for reducing excessive alcohol use in your community.

 

Reducing Indoor Tanning Among Minors

 

Indoor tanning increases a person’s risk of skin cancer and is especially risky for young people. Public health efforts by state and local agencies can protect young people from the harms of indoor tanning.

 

These efforts range from communication and educational strategies that increase knowledge and awareness to research and surveillance that can support strategies to restrict youth access to indoor tanning.

 

Reducing Indoor Tanning Among Minors provides information about indoor tanning among minors and potential strategies for reducing indoor tanning among minors in your community.

 

How to Reduce Radon in Homes

 

Radon is a radioactive gas that occurs naturally in nearly all soil. It enters homes and other buildings through small cracks and holes in the foundation, where it becomes trapped and accumulates in the air.

 

When people breathe in radon, it damages the lungs, which can lead to lung cancer. According the U.S. Environmental Protection Agency, radon is the leading cause of lung cancer among non-smokers and the second leading cause of lung cancer among smokers in the United States. This promising practices brief explains how to reduce radon in homes, and what states and comprehensive cancer control programs can do about radon.

 

Best Practices for Comprehensive Tobacco Control Programs

 

Tobacco use is the single most preventable cause of disease, disability, and death in the United States.

 

Nearly half a million Americans die from tobacco use each year, and more than 16 million suffer from a disease caused by smoking.

 

Despite these risks, about 42 million U.S. adults still smoke. This evidence-based guide, created by CDC’s Office on Smoking and Health, helps states plan and establish effective tobacco control programs to prevent and reduce tobacco use.

More Information

Cancer Prevention Among Youth

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Carcinogenesis

 

KEY POINTS

Carcinogenesis is the process in which normal cells turn into cancer cells.

Changes (mutations) in genes occur during carcinogenesis.

 

Carcinogenesis is the process in which normal cells turn into cancer cells.

 

  • Carcinogenesis is the series of steps that take place as a normal cell becomes a cancer Cells are the smallest units of the body and they make up the body’s tissues.

 

  • Each cell contains genes that guide the way the body grows, develops, and repairs itself.

 

  • There are many genes that control whether a cell lives or dies, divides (multiplies), or takes on special functions, such as becoming a nerve cell or a muscle cell.

 

Changes (mutations) in genes occur during carcinogenesis.

 

Changes (mutations) in genes can cause normal controls in cells to break down. When this happens, cells do not die when they should and new cells are produced when the body does not need them. The buildup of extra cells may cause a mass (tumor) to form.

 

Tumors can be benign or malignant (cancerous). Malignant tumor cells invade nearby tissues and spread to other parts of the body. Benign tumor cells do not invade nearby tissues or spread.

 

Cancer prevention: 7 tips to reduce your risk

 

Concerned about cancer prevention? Take charge by making changes such as eating a healthy diet and getting regular screenings.

 

By Mayo Clinic Staff

 

You’ve probably heard conflicting reports about cancer prevention. Sometimes the specific cancer-prevention tip recommended in one study or news report is advised against in another.

 

In many cases, what is known about cancer prevention is still evolving. However, it’s well-accepted that your chances of developing cancer are affected by the lifestyle choices you make.

 

So if you’re concerned about cancer prevention, take comfort in the fact that some simple lifestyle changes can make a big difference. Consider these seven cancer prevention tips.

 

  1. Don’t use tobacco

 

Using any type of tobacco puts you on a collision course with cancer. Smoking has been linked to various types of cancer — including cancer of the lung, mouth, throat, larynx, pancreas, bladder, cervix and kidney. Xhewing tobacco has been linked to cancer of the oral cavity and pancreas. Even if you don’t use tobacco, exposure to secondhand smoke might increase your risk of lung cancer.

 

Avoiding tobacco — or deciding to stop using it — is one of the most important health decisions you can make. It’s also an important part of cancer prevention. If you need help quitting tobacco, ask your doctor about stop-smoking products and other strategies for quitting.

 

 

  1. Eat a healthy diet

 

Although making healthy selections at the grocery store and at mealtime can’t guarantee cancer prevention, it might help reduce your risk. Consider these guidelines:

  • Eat plenty of fruits and vegetables. Base your diet on fruits, vegetables and other foods from plant sources — such as whole grains and beans.
  • Avoid obesity. Eat lighter and leaner by choosing fewer high-calorie foods, including refined sugars and fat from animal sources.
  • If you choose to drink alcohol, do so only in moderation. The risk of various types of cancer — including cancer of the breast, colon, lung, kidney and liver — increases with the amount of alcohol you drink and the length of time you’ve been drinking regularly.
  • Limit processed meats. A report from the International Agency for Research on Cancer, the cancer agency of the World Health Organization, concluded that eating large amounts of processed meat can slightly increase the risk of certain types of cancer.

 

In addition, women who eat a Mediterranean diet supplemented with extra-virgin olive oil and mixed nuts might have a reduced risk of breast cancer. The Mediterranean diet focuses on mostly on plant-based foods, such as fruits and vegetables, whole grains, legumes and nuts. People who follow the Mediterranean diet choose healthy fats, like olive oil, over butter and fish instead of red meat.

 

  1. Maintain a healthy weight and be physically active

 

Maintaining a healthy weight might lower the risk of various types of cancer, including cancer of the breast, prostate, lung, colon and kidney.

 

Physical activity counts, too. In addition to helping you control your weight, physical activity on its own might lower the risk of breast cancer and colon cancer.

 

Adults who participate in any amount of physical activity gain some health benefits. But for substantial health benefits, strive to get at least 150 minutes a week of moderate aerobic activity or 75 minutes a week of vigorous aerobic physical activity. You can also do a combination of moderate and vigorous activity.

 

As a general goal, include at least 30 minutes of physical activity in your daily routine — and if you can do more, even better.

 

What Is Cancer?

Cancer is a term used for diseases in which abnormal cells divide without control and can invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. Cancer is not just one disease, but many diseases. There are more than 100 kinds of cancer. For more information, visit the National Cancer Institute’s What Is Cancer?

 

Kinds of Cancer

  • Bladder cancer risk factors include smoking, genetic mutations, and exposure to certain chemicals.
  • Breast cancer is the most common cancer among American women. Getting mammograms regularly can lower the risk of dying from breast cancer. Talk to your doctor about when to start and how often to get a screening mammogram.

 

  • Cervical cancer is highly preventable in most Western countries because screening tests and a vaccine to prevent human papillomavirus (HPV) infections, which cause most cervical cancers, are available.
  • Of cancers affecting both men and women, colorectal cancer (cancer of the colon and rectum) is the second leading cancer killer in the United States, but it doesn’t have to be. If you are 50 years old or older, get screened now.
  • Smoking is the most important risk factor for kidney and renal pelvis cancers. To lower your risk, don’t smoke, or quit if you do. Be very careful if you work with the chemical trichloroethylene.
  • To lower your risk for liver cancer, get vaccinated against Hepatitis B, get tested for Hepatitis C, and avoid drinking too much alcohol.
  • Lung cancer is the leading cause of cancer death and the second most common cancer among both men and women in the United States. The most important thing you can do to lower your lung cancer risk is to quit smoking and avoid secondhand smoke.
  • Ovarian cancer causes more deaths than any other cancer of the female reproductive system. But when ovarian cancer is found in its early stages, treatment works best.
  • Prostate cancer is the most common cancer among American men. Most prostate cancers grow slowly, and don’t cause any health problems in men who have them. Learn more and talk to your doctor before you decide to get tested or treated for prostate cancer.
  • Skin cancer is the most common cancer in the United States. Most cases of melanoma, the deadliest kind of skin cancer, are caused by exposure to ultraviolet (UV) light. To lower your skin cancer risk, protect your skin from the sun and avoid indoor tanning.
  • Uterine cancer is the fourth most common cancer in women in the United States and the most commonly diagnosed gynecologic cancer.

Vaginal and vulvar cancers are rare, but all women are at risk for these cancers.

 

How Can Cancer Be Prevented?

 

The number of new cancer cases can be reduced and many cancer deaths can be prevented.

 

Research shows that screening for cervical and colorectal cancers as recommended helps prevent these diseases by finding precancerous lesions so they can be treated before they become cancerous.

 

Screening for cervical, colorectal, and breast cancers also helps find these diseases at an early stage, when treatment works best. CDC offers free or low-cost mammograms and Pap tests nationwide, and free or low-cost colorectal cancer screening in six states.

 

Vaccines (shots) also help lower cancer risk. The human papillomavirus (HPV) vaccine helps prevent most cervical cancers and several other kinds of cancer, and the hepatitis B vaccine can help lower liver cancer risk.

 

A person’s cancer risk can be reduced with healthy choices like avoiding tobacco, limiting alcohol use, protecting your skin from the sun and avoiding indoor tanning, eating a diet rich in fruits and vegetables, keeping a healthy weight, and being physically active.

 

 

 

 

  1. Remember to ask!

Common Questions

 

What Should I Know About Screening?

 

Cervical cancer is the easiest gynecologic cancer to prevent, with regular screening tests and follow-up. Two screening tests can help prevent cervical cancer or find it early—

  • The Pap test (or Pap smear) looks for precancers, cell changes on the cervix that might become cervical cancer if they are not treated appropriately.

 

The Pap test is recommended for all women between the ages of 21 and 65 years old, and can be done in a doctor’s office or clinic. During the Pap test, the doctor will use a plastic or metal instrument, called a speculum, to widen your vagina. This helps the doctor examine the vagina and the cervix, and collect a few cells and mucus from the cervix and the area around it. The cells are then placed on a slide or in a bottle of liquid and sent to a laboratory. The laboratory will check to be sure that the cells are normal.

How to Prepare for Your Pap Test

You should not schedule your Pap test for a time when you are having your period. If you are going to have a Pap test in the next two days—

  • You should not douche (rinse the vagina with water or another fluid).
  • You should not use a tampon.
  • You should not have sex.
  • You should not use a birth control foam, cream, or jelly.
  • You should not use a medicine or cream in your vagina.

If you get the HPV test along with the Pap test, the cells collected during the Pap test will be tested for HPV at the laboratory. Talk with your doctor, nurse, or other health care professional about whether the HPV test is right for you.

When you have a Pap test, the doctor may also perform a pelvic exam, checking your uterus, ovaries, and other organs to make sure there are no problems. There are times when your doctor may perform a pelvic exam without giving you a Pap test. Ask your doctor which tests you are having, if you are unsure.

If you have a low income or do not have health insurance, you may be able to get a free or low-cost Pap test through the National Breast and Cervical Cancer Early Detection Program. Find out if you qualify.

 

When to Get Screened

 

You should start getting regular Pap tests at age 21. The Pap test, which screens for cervical cancer, is one of the most reliable and effective cancer screening tests available.

 

The only cancer for which the Pap test screens is cervical cancer. It does not screen for ovarian, uterine, vaginal, or vulvar cancers. So even if you have a Pap test regularly, if you notice any signs or symptoms that are unusual for you, see a doctor to find out why you’re having them. If your Pap test results are normal, your doctor may tell you that you can wait three years until your next Pap test.

Prevent Cervical Cancer with the Right Test at the Right Time infographic

 

If you are 30 years old or older, you may choose to have an HPV test along with the Pap test. Both tests can be performed by your doctor at the same time. When both tests are performed together, it is called co-testing. If your test results are normal, your chance of getting cervical cancer in the next few years is very low. Your doctor may then tell you that you can wait as long as five years for your next screening. But you should still go to the doctor regularly for a checkup.

 

If you are 21 to 65 years old, it is important for you to continue getting a Pap test as directed by your doctor—even if you think you are too old to have a child or are not having sex anymore. If you are older than 65 and have had normal Pap test results for several years, or if you have had your cervix removed as part of a total hysterectomy for non-cancerous conditions, like fibroids, your doctor may tell you that you do not need to have a Pap test anymore.

Test Results

It can take as long as three weeks to receive your test results. If your test shows that something might not be normal, your doctor will contact you and figure out how best to follow up. There are many reasons why test results might not be normal. It usually does not mean you have cancer.

 

If your test results show cells that are not normal and may become cancer, your doctor will let you know if you need to be treated. In most cases, treatment prevents cervical cancer from developing. It is important to follow up with your doctor right away to learn more about your test results and receive any treatment that may be needed.

 

Cervical Cancer Screening Guidelines

 

The Cervical Cancer Screening Guidelines chart[PDF-175KB] compares recommendations from the American Cancer Society, U.S. Preventive Services Task Force, and the American College of Obstetricians and Gynecologists regarding—

  • When to start screening.
  • Screening methods and intervals.
  • When to stop screening.
  • Screening after a total hysterectomy.
  • Pelvic exams.

Screening among women who have been vaccinated against human papillomavirus (HPV).

 

 

Stem Cells International

Volume 2012 (2012), Article ID 367567, 9 pages

http://dx.doi.org/10.1155/2012/367567

 

Review Article

Stem Cell Niche Dynamics: From Homeostasis to Carcinogenesis

 

Kevin S. Tieu,1 Ryan S. Tieu,1 Julian A. Martinez-Agosto,2 and Mary E. Sehl3

1Computational and Systems Biology Interdepartmental Program, School of Medicine, University of California, Los Angeles, CA 90095, USA

2Department of Human Genetics, School of Medicine, University of California, Los Angeles, CA 90095, USA

3Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California, Los Angeles, P.O. Box 957059, Suite 2333 PVUB, Los Angeles, CA 90095-7059, USA

 

Received 7 June 2011; Accepted 23 October 2011

Academic Editor: Linheng Li

Copyright © 2012 Kevin S. Tieu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

Abstract

 

The stem cell microenvironment is involved in regulating the fate of the stem cell with respect to self-renewal, quiescence, and differentiation.

 

Mathematical models are helpful in understanding how key pathways regulate the dynamics of stem cell maintenance and homeostasis.

 

This tight regulation and maintenance of stem cell number is thought to break down during carcinogenesis. As a result, the stem cell niche has become a novel target of cancer therapeutics.

 

Developing a quantitative understanding of the regulatory pathways that guide stem cell behavior will be vital to understanding how these systems change under conditions of stress, inflammation, and cancer initiation. Predictions from mathematical modeling can be used as a clinical tool to guide therapy design.

 

We present a survey of mathematical models used to study stem cell population dynamics and stem cell niche regulation, both in the hematopoietic system and other tissues. Highlighting the quantitative aspects of stem cell biology, we describe compelling questions that can be addressed with modeling. Finally, we discuss experimental systems, most notably Drosophila, that can best be used to validate mathematical predictions.

 

  1. Introduction

 

The hematopoietic stem cell niche is an important regulator of stem cell fate. There are complex signaling pathways, such as Notch, Wnt, and Hedgehog, that carefully regulate stem cell renewal, differentiation, and quiescence [1–3]. Mathematical models can be useful in studying the dynamics of stem cell maintenance.

 

Quantitative models can provide information about cell population dynamics, regulatory feedback of interacting networks, and spatial considerations related to the structural relationships between stem cells and their progeny with cells of the microenvironment.

 

Errors in stem cell division rate or in the balance between self-renewal and differentiation may result in tissue overgrowth or depletion [4]. One novel target of cancer therapeutics is the stem cell niche [5, 6]. Stem cell niche signaling inhibitors are being designed with the idea that regulatory signals that are active in stem cell niche homeostasis may go awry during carcinogenesis [6–8].

 

Understanding the biology and dynamics of stem cell behavior under normal conditions and examining how the dynamics change under conditions of stress is essential to our understanding of how these mechanisms might change during carcinogenesis.

 

Mathematical and physical models have been used to study stem cell population dynamics and the regulation of stem cell fate through niche signaling with great success. We present a review of quantitative approaches to understanding stem cell niche signaling in the hematopoietic system, as well as in other tissues under conditions of homeostasis and carcinogenesis.

 

We explain the benefits of mathematical models in advancing our understanding of the mechanisms of regulation of stem cell fate and how this regulation changes in cancer development. We describe models that incorporate spatial aspects of the regulation of asymmetric division and compare normal conditions to carcinogenesis. We highlight the synergistic relationship between mathematical predictions and experimental validation and illustrate Drosophila as a model system for quantitative studies of the stem cell niche. Finally, we address the potential for mathematical models to predict and optimize therapies targeting the stem cell niche.

 

  1. Quantitative Aspects of the Hematopoietic Stem Cell Niche Hematopoietic stem cells (HSCs) are a dynamically well-characterized stem cell population. The hematopoietic system was the first system in which multipotency, or the ability for a single HSC to regenerate all of the different cell types within the tissue, was described.

 

A second defining characteristic for stem cells, self-renewal, has also been demonstrated in HSCs. Self-renewal is the ability of the HSC to generate a genetically identical copy of itself during cell division. This can occur asymmetrically, giving rise to one identical copy and one partially differentiated daughter cell, or symmetrically, giving rise to two identical copies of itself. Single HSCs have been shown to be self-renewing, multipotent, and to cycle with slow kinetics. Extrapolation from feline and murine data suggests a symmetric birth rate for human HSCs of once every 42 weeks [9].

 

Quiescence, the state of not dividing, allows HSCs to avoid mutation accumulation and contributes to their long lifespan. In contrast to senescence, where the cell loses its ability to undergo division, a cell can reawaken from the state of quiescence to an activated state where it can again undergo self-renewal.

 

The stem cell microenvironment regulates stem cell self-renewal, differentiation, quiescence, and activation. While little in situ information is known about the anatomy and structural relationships of the hematopoietic stem cell and its niche, there is a growing amount of experimental information about the behavior of signaling systems that govern HSC fate.

 

Population dynamics models have been successfully used to model the human hematopoietic system in both health and disease [9–17]. Using stochastic and deterministic models, significant progress has been made in understanding the dynamics of cancer initiation and progression [18, 19] and the sequential order of mutation accumulation [20]. Mathematical models have also been useful in modeling leukemic stem cell and progenitor population changes in response to therapy and the development of resistance [14].

 

An ongoing debate in hematopoietic stem cell biology concerns how much variability exists in hematopoietic stem cell fate [21]. Stochastic models have been used to study the dynamics of clonal repopulation [22] following hematopoietic stem cell transplant.

In these models, trajectories of hematopoietic stem cell counts as well as progenitor and differentiated cell counts are generated and compared with observed cell counts. Rates of self-renewal, differentiation, and elimination of cells are estimated. Stochastic trajectories are found to match experimental results. These models predict that hematopoiesis is probabilistic in nature and that clonal dominance can occur by chance.

 

These models could be enhanced by examining regulators of stem cell fate by the microenvironment. Stochastic simulation can be used to incorporate elements of the stem cell niche, such as surrounding stromal cells and signaling pathways, and model cell-cell and cell-environment interactions. These models could identify regulators of stem cell fate and explore the dynamics of this regulation.

 

Chronic myelogenous leukemia (CML) represents a nice system to quantitatively study hematopoietic stem cell and progenitor dynamics. CML is the first malignancy recognized as a stem cell disorder. The translocation t(9;22) is present in leukemic stem cells, multipotent progenitors, and their progeny of the myeloid lineage. This translocation leads to transcription of the BCR-ABL fusion oncogene which is thought to regulate cell survival.

 

Therapy inhibiting BCR-ABL is one of the first examples where chronic administration of a molecularly targeted therapy has led to a dramatic clinical response. This response is observed in all phases of the disease.

 

Mathematical models have been used to demonstrate that leukemic stem cells are not targeted by imatinib therapy [14], and that successful therapy must target leukemic stem cells [12]. Other models have highlighted the importance of leukemic stem cell quiescence as a mechanism leading to therapeutic resistance [13].

 

In a study of chronic myelogenous leukemia under targeted therapy, Michor et al. [14] describe the dynamics of leukemic stem cells and the development of resistance using a Moran process model. Based on calculated rates of death and differentiation using data of biphasic decline of BCR-ABL transcripts, they conclude that the leukemic stem cell compartment is not sensitive to therapy. An alternative explanation is provided by Komarova and Wodarz [13], using a stochastic model in which quiescence and reactivation of leukemic stem cells are considered. In this work, the biphasic decline of BCR-ABL transcripts is explained by the elimination of active leukemic stem cells, followed by the slower elimination of quiescent leukemic stem cells following their reactivation.

 

This study offers hope that targeted therapy, used in combination with potential therapies that lead to activation of quiescent cells, could eradicate the stem cell-like compartment of a tumor.

 

These models could be expanded by modeling the contribution of the microenvironment that regulates quiescence and activation of stem cells. Validation of these models will require experimental determination of rates of quiescence and reactivation to obtain accurate parameters for modeling.

 

Birth-death process models have been used to study extinction of leukemic and normal hematopoietic stem cells under therapy targeting leukemic stem cells. These models conclude that the killing efficiency of a therapy is a major determinant of the mean time to extinction of leukemic stem cells (optimal duration), while the selectivity of a therapy predicts the average number of normal hematopoietic stem cells at the time of leukemic stem cell extinction (safety) [23]. Incorporating quiescence in these models reveals that a successful therapy needs to target both active and quiescent leukemic stem cells.

 

We extended this model to consider combination of therapy targeting leukemic stem cells, and their niche was considered using stochastic simulation. Because stem cell self-renewal is expected to decrease with Wnt-inhibitor therapy, we modeled the addition of niche-targeted therapy as a decrease in birth rates of leukemic stem cells. We found that this combination can be effective in eliminating the leukemic stem cell compartment, even when the effects of BCR-ABL-targeted therapy on stem cells are modest.

 

We anticipate that extension of these models to include regulatory feedback of the stem cell microenvironment using stochastic reaction kinetic methods would be very helpful in modeling dynamics of niche-targeted therapies.

 

The hematopoietic stem cell niche has been studied in the healthy hematopoietic system. A model based on self-organizing principles demonstrates the importance of asymmetry in determining stem cell fate and concludes that stem cell fate is only predictable in describing populations rather than individual cellular fates [24].

 

Deterministic models are useful in simulating proliferation and differentiation of all populations comprising the stem cell niche [25]. These studies conclude that kinetics are highly variable because of the relatively small number of cells proliferating and differentiating in the niche.

 

Experimental studies have examined the role of Wnt signaling in regulation of normal hematopoietic regeneration [26]. We expect the combination of mathematical modeling with experimental validation to prove useful in modeling the pathways under normal conditions and dysregulation of these pathways during stress, inflammation, and carcinogenesis.

 

Figure 1 describes the elements of the HSC niche and an accompanying schematic representation of a mathematical model of the niche. The model captures the key regulatory components of niche dynamics, including cell population sizes and the signaling pathways that regulate them.

Figure 1: Quantitative aspects of the hematopoietic stem cell (HSC) niche. The left panel provides a structural picture of the niche, while the right panel shows a schematic representation of a mathematical model for the regulation of hematopoietic stem cell fate.

 

The model incorporates population counts and signaling pathways that may play a role in regulating stem cell population dynamics. Cellular populations comprising the bone and vascular niches include osteoblasts (OBs), endothelial cells, HSCs, multipotent progenitors (MPPs), common myeloid progenitors (CMPs), common lymphoid progenitors(CLPs), and differentiated cells. Signaling from Wnt, β-catenin, p21, p18, and bmi-1 regulate self-renewal, while Notch and GSK3 feedback from progenitors inhibit differentiation that usually accompanies self-renewal. Signaling from osteoblasts includes osteopontin (Opn) expression that inhibits HSC self-renewal, parathyroid hormone-related protein (PPR) which increases HSCs, N-cadherin which binds β-catenin, and Tie2/angiopoietin which regulates quiescence.

 

  1. Drosophila as a Classic Model System

Drosophila represents an excellent model system to study stem cells, their microenvironment, and the tight regulation of homeostasis through different signaling pathways.

 

The male Drosophila germ line population is a classic system used to study properties of the stem cell niche [27, 28]. The power of this model includes the ability to quantify cell populations over time, the relatively quick repletion of lost cells with newly differentiated cells, and the ability to experimentally observe spatial effects.

 

These quantitative aspects, as well as its simple, well-characterized lineages, make the Drosophila experimental system ideally suited for the development and validation of mathematical modeling. Finally, vertebrate and invertebrate digestive systems show extensive similarities in their developments, cellular makeup, and genetic control [29].

 

Mathematical and physical models have been used to study regulation of stem cell fate through niche signaling in the Drosophila blood and midgut [30], as well as in the Drosophila eye [31] and the Drosophila embryo [32], with great success. Studies of the stem cell niche in model systems such as Drosophila have revealed adhesive interactions, cell cycle modifications, and intercellular signals that operate to control stem cell behavior [4, 33].

 

These interactions have been studied quantitatively. For example, Wnt and Notch play pivotal roles in stem cell regulation in the Drosophila intestine [30, 34]. In addition, the APC gene has been shown to regulate Drosophila intestinal stem cell proliferation [35]. APC is well known to play a role in human colon carcinogenesis, and mathematical models have shown that stem cell proliferation leads to colon tumor formation in humans [36, 37].

 

 

The spatially patterned self-renewal and differentiation of stem cells has been extensively studied in Drosophila embryonic studies of development [32, 38–40]. The spatial orientation of stem cells has been visualized in Drosophila brain and testes and has recently been shown to be of great importance in experimental models of neuroblastoma growth in Drosophila [41].

 

We anticipate that the combination of spatial effects simulation and direct visualization of the Drosophila midgut through experiment will advance our understanding of the interaction of alterations in signaling pathways and spatial effects in carcinogenesis.

 

  1. Extension to Inflammation and Carcinogenesis across Tissues

Unifying features of stem cell niche regulation are observed across tissues and across organisms [42, 43]. Figures 1, 2, and 3 compare the structural and signaling elements of the stem cell niche across the hematopoietic, intestine, and breast tissues.

 

While little is known about the structural orientation of the human hematopoietic stem cell niche 1, much has been learned about the signaling pathways in both the bone and vasculature that regulate HSC fate. Osteoblasts (OBs) express osteopontin which negatively regulates HSC proliferation.

 

Tie2/angiopoietin signaling regulates HSC anchorage and quiescence, and adherence to osteoblasts. HSCs and OBs are increased via the parathyroid hormone-related protein receptor (PPR) expressed in OBs. OBs express N-cadherin which forms a beta-catenin adherens complex with HSCs. C-myc negatively regulates N-cadherin in differentiating HSCs and promotes differentiation and displacement from the endosteum.

 

OBs express Jagged-1, a Notch receptor that when bound inhibits differentiation that usually accompanies Wnt-induced HSC proliferation. GSK-3 activity enhances HSC progenitor activity and may control asymmetric cell division by modulating Notch and Wnt signaling pathways.

 

 

Figure 2: Structural and dynamic aspects of the Drosophila intestinal stem cell (ISC) niche. The left panel shows a structural picture of the Drosophila intestine, while the right panel reveals population and regulatory elements of a mathematical model for ISC regulation.

 

Populations of the intestinal stem cell niche in the Drosophila include ISCs, enteroblasts (EBs), enteroendocrine cells (EE), and enterocytes (ECs). Wnt signaling from underlying smooth muscle and Notch feedback from EB regulate ISC self-renewal, while Jak/Stat feedback from damaged ECs increases ISC self-renewal.

Figure 3: Model of the breast stem cell niche including structural elements (left panel) and mathematical model (right panel). Key populations of the mammary stem cell niche include mammary stem cells (MSCs), mesenchymal stem cells, endothelial stem cells (ESCs), bipotent progenitor (BPP), luminal progenitor (LP), myoepithelial progenitor (MEP), myoepithelial cells (MCs), luminal epithelial cells (LCs), and stromal cells. Wnt, Notch, and Hedgehog (Hh) signaling play a role in MSC self-renewal. Regulatory signals from growth factors (GFs) secreted by fibroblasts and CCL signaling from mesenchymal stem cells also regulate MSC fate.

 

Figure 2 depicts the intestinal stem cell niche of Drosophila. Here, we see four key cellular populations: intestinal stem cells (ISCs), enteroblasts (EBs), enterocytes (ECs), and enteroendocrine (EE) cells. It has been previously established that ISCs can self-renew under the influence of the Wnt signaling pathway [44] and can asymmetrically divide giving rise to one partially differentiated EB cell and one ISC, under the influence of the Delta/Notch signaling pathway. EBs can then differentiate into either EC cells or EE cells.

 

There is feedback from the EB population to the ISC population, which inhibits self-renewal and differentiation, in order to maintain stable population sizes under the normal conditions of homeostasis [45]. The EC population also interacts with the ISC population via Jak/Stat signaling feedback, which increases self-renewal and differentiation, in conditions when EC loss occurs [45].

 

Finally, both structural and signaling aspects of the breast stem cell niche are shown in Figure 3. The hedgehog (Hh) pathway is required for normal development of the mammary gland and regulates self-renewal of human mammary stem cells (MSCs) [46–48]. Hh also targets endothelial cells and induces angiogenesis by promoting endothelial progenitor proliferation and migration.

 

Wnt signaling regulates proliferation, apoptosis, and differentiation and maintains stem cells in a self-renewing state. Notch promotes self-renewal in normal mammary stem cells [46, 49]. Notch3 is expressed in epithelial progenitors, and Notch4 is expressed in bipotent progenitors. Markers of mammary stem cells include ALDH1 expression, and Sca-1. There is a significant correlation between expression of ALDH1 and HER2 overexpression [50].

 

The common signaling pathways that control stem cell self-renewal in these pathways, such as Notch, Wnt, and Hedgehog, are known to play a role in carcinogenesis [2, 41]. A growing body of evidence from a variety of solid tumors suggests that the first carcinogenic cell within a tumor possesses stem cell properties, including self-renewal, increased cell survival, limitless replicative potential, and the ability to produce differentiating cells [51–60].

 

However, it is unclear whether accumulation of mutations within a tumor cell with stem cell properties or extrinsic factors originating in the tumor microenvironment drive tumor progression [61, 62]. Understanding niche signaling pathways under normal conditions, and in response to inflammation and stress response, is vital to understanding how they may go awry in carcinogenesis.

 

The known link between inflammation and cancer may involve the regulation of stem cell fate by inflammatory cytokines [63]. IL-1, IL-6, and IL-8 are known to activate Stat3/NF-κB pathways in tumor and stromal cells. Positive feedback loops are formed involving further cytokine production which can drive cancer stem cell self-renewal [63]. These networks can be nicely modeled using stochastic reaction kinetics. Predictions from these models could be used to guide therapy design.

Dysregulation of normal homeostatic processes in the human hematopoietic stem cell niche may lead to enhanced self-renewal and proliferation, enforced quiescence, and resistance to chemotherapeutic agents. Leukemic stem cells have been shown to infiltrate the normal HSC niche by direct invasion or secretion of substances such as stem cell factor [6]. Leukemic stem cells may also exhibit dysregulated homing and engraftment, leading to alternative niche formation [6]. Future mathematical models of leukemic stem cell dynamics should take into account the stem cell niche.

 

Cytokine/Jak/Stat signaling has recently been shown to mediate regeneration and response to stress in the Drosophila midgut [45, 64]. Mathematical models of proliferation and differentiation of Drosophila intestinal stem cells have examined the dynamics of Wnt and Notch signaling [30], but have not yet examined the feedback of Jak/Stat signaling from the differentiated enterocytes to intestinal stem cells. Mathematical models of the human intestinal stem cell niche have shown that dysregulated colonic crypt dynamics cases stem cell overpopulation and initiate colon cancer [36]. Symmetric division of cancer stem cells has been shown to be a key mechanism of tumor growth to target in therapeutic approaches [37].

 

In mammalian systems, MyD88 and RAS signaling have been shown to lead to mouse and human cell transformation [65]. These signaling pathways are known to be involved with inflammation and also play a direct role in cell cycle control.

 

The link between inflammation and carcinogenesis needs to be studied quantitatively.

 

Alterations in Wnt signaling contribute to excess proliferation of mammary progenitor cells leading to cancer [66]. Unregulated Notch signaling in the mouse mammary gland leads to tumor formation. Increased expression of Notch in ductal carcinoma is associated with shorter time to recurrence [67].

 

Breast density is an important risk factor for breast tumor development [68], suggesting a role of the stem cell microenvironment in carcinogenesis. Growth factors secreted by fibroblasts influence mammary stem cell behavior. Endothelial cell and adipocytes may also influence stem cell behavior. CCL5 secretion by mesenchymal stem cells influences stem cell self-renewal. Alterations in Notch signaling are thought to play a role in breast cancer development.

 

Combination of theory and experiment has shed light on stromal-tumor interactions in the human breast [69]. In the breast, ductal cells secrete TGF-beta and fibroblasts secrete EGF. During carcinogenesis, TGF-beta then transforms fibroblasts into myofibroblasts, which in turn secrete higher EGF. Mathematical modeling has shown that this feedback system increases proliferation of tumor cells, and theoretical results match experimental validation well.

 

Mathematical models have also shed light on the interactions between the stem and nonstem compartments of solid tumors and their effects on the heterogeneous growth of solid tumors. These models show that apoptosis of nonstem cells paradoxically leads to tumor growth and progression [70, 71].

 

Cancer cell plasticity is an important consideration in the study cancer stem-like cells in oncology. The finding that nonstem cells can dedifferentiate to a stem-like state in mammary cell lines [72] has important implications in defining cancer stem-like cells and identifying therapies to target them. Markov models have recently proven very helpful in calculating rates of dedifferentiation of mammary epithelial cells to stem-like cells [73]. Consideration of microenvironmental signaling that regulates these transitions will greatly enhance these models and their predictions.

 

  1. Spatial Considerations in Modeling Stem Cell Regulation

Spindle orientation is well known to play a role in stem cell fate [74]. Asymmetric division is regulated by maintaining the stem cell orientation, and this is regulated by its spatial relationship with the cells of the niche. Induction of brain tumor growth has been demonstrated by altering stem-cell asymmetric division in Drosophila melanogaster [41].

 

Loss of cell polarity and cancer are tightly correlated [4]. In stem cells, loss of polarity leads to impairment of asymmetric cell division, altering cell fates, rendering daughter cells unable to respond to the mechanisms that control proliferation. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells [75]. Figure 4 displays regulation of stem cell asymmetric division under normal homeostatic conditions and the loss of this regulation during carcinogenesis. Labeling of template strands in stem cells of small intestine crypts using tritiated thymidine reveals selective retention of parental DNA strands and loss of newly synthesized strands during stem cell division [76].

 

This mechanism provides the stem cell with protection from DNA replication errors during asymmetric division. Loss of asymmetric division may lead to loss of this protection against chromosomal instability.

Figure 4: Stem cell polarity: homeostasis and dysregulation. Regulation of asymmetric division in the stem cell niche. The left panel represents spatial regulation of normal homeostasis, while the right panel demonstrates the loss of this asymmetry during carcinogenesis.

Mathematical models that allow for the inclusion of spatial effects are necessary in order to study this loss of asymmetry in the stem cell and its relation to carcinogenesis. Classic models of spatial effects on development in Drosophila have examined reaction diffusion equations [38, 39]. While multiscale models are more recently being used to study complex biologic systems and their genetic regulation, most of the methods used assume a well-stirred system and have not allowed for consideration of spatial effects until recently. Incorporating a spatial component into stochastic simulation methods is an exciting frontier in stochastic reaction kinetics [77, 78]. A stochastic reaction-diffusion equation is used in place of the chemical master equation and is sampled in the stochastic simulation. These methods have been shown to be successful in modeling spatial effects in genetic regulatory networks [78].

 

  1. Conclusions

Mathematical models have proven useful in characterizing stem cell and progenitor cell population dynamics, and in understanding the interacting components of the stem cell niche. Identifying quantitative characteristics of the stem cell microenvironment that are generalizable across tissues, as well as those distinct to each system, will be necessary to help define the emerging concept of the stem cell niche.

 

 

 

Modeling the components of the stem cell niche and their interactions will advance our understanding of the tight regulation of stem cell fate. In turn, it will allow us to predict and validate responses to stress, inflammation, and carcinogenesis. In addition to quantifying population distributions and feedback networks, it will be necessary and informative to incorporate spatial aspects that govern asymmetric versus symmetric stem cell self-renewal.

 

We expect that the combination of predictive modeling and experimental validation will prove useful in our understanding of the regulatory components of stem cell maintenance and the changes that occur in response to treatments designed to target the stem cell niche.

 

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Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis

  1. Bernard Weinstein

+

Author Affiliations

  • Herbert Irving Comprehensive Cancer Center and Departments of Medicine, Genetics and Development and Public Health, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA
  • Received February 8, 2000.
  • Accepted February 8, 2000.

 

Abstract

The multistage process of carcinogenesis involves the progressive acquisition of mutations, and epigenetic abnormalities in the expression, of multiple genes that have highly diverse functions. An important group of these genes are involved in cell cycle control.

 

Thus, cyclin D1 is frequently overexpressed in a variety of human cancers. Cylin D1 plays a critical role in carcinogenesis because (i) overexpression enhances cell transformation and tumorigenesis, and enhances the amplification of other genes, and (ii) an antisense cyclin D1 cDNA reverts the malignant phenotype of carcinoma cells.

 

Therefore, cyclin D1 may be a useful biomarker in molecular epidemiology studies, and inhibitors of its function may be useful in both cancer chemoprevention and therapy. We discovered a paradoxical increase in the cell cycle inhibitors protein p27Kip1 in a subset of human cancers, and obtained evidence for homeostatic feedback loops between cyclins D1 or E and p27Kip1.

 

Furthermore, derivatives of HT29 colon cancer cells with increased levels of p27Kip1 showed increased sensitivity to induction of differentiation. This may explain why decreased p27Kip1 in a subset of human cancers is associated with a high grade (poorly differentiated) histology and poor prognosis. Agents that increase cellular levels of p27Kip1 may, therefore, also be useful in cancer therapy. Using an antisense Rb oligonucleotide we obtained evidence that the paradoxical increase in pRb often seen in human colon cancers protects these cells from growth inhibition and apopotosis.

 

On the basis of these, and other findings, we hypothesize that homeostatic feedback mechanisms play a critical role in multistage carcinogenesis. Furthermore, because of their bizarre circuitry, cancer cells suffer from gene addiction' andgene hypersensitivity’ disorders that might be exploited in both cancer prevention and chemotherapy.

Key words

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The current paradigm of multistage carcinogenesis

 

A variety of experimental and clinical studies carried out during the past century established the principle that cancers develop through a multistage process which can encompass an appreciable fraction of the lifespan of the species (1–3). Within the past few decades astounding progress has been made in our understanding of the cellular, biochemical and molecular genetic events that occur during this multistage process.

 

A current paradigm is that this stepwise process reflects the progressive acquisition of activating mutations in dominant acting growth enhancing genes (oncogenes) and inactivating recessive mutations in growth inhibitory genes (tumor suppressor genes) (4). It is also apparent that epigenetic abnormalities in the expression of these genes also play an important role in carcinogenesis (1–3).

 

 

Following the initial discovery of oncogenes, ~20 years ago, it appeared that there might be a small number of such genes. However, since then over 100 oncogenes and at least 12 tumor suppressor genes have been identified, and the list keeps growing (5–7). Moreover, a single colon cancer cell frequently contains defined mutations in multiple genes (four or more) plus numerous less well defined mutant and/or aberrantly expressed genes, as well as gross chromosomal abnormalities.

 

Indeed, in human colon tumors ~25% of all loci show loss of heterozygosity, and in cancer cells with defects in DNA mismatch repair thousands of loci can be mutated in a single cancer cell (6,8,9). Presumably, these widespread changes reflect the deleterious effects of mutagens, both exogenous and endogenous, as well as various types of genomic instability acquired during tumor development. In the subset of familial cancers some of these mutations, usually in tumor suppressor genes, are inherited, thus enhancing the multistage process of carcinogenesis.

 

 

Because of the large number and diverse functions of the known oncogenes and tumor suppressor genes we have developed a classification scheme which is based on their specific biochemical functions (Table I) (10). The genes are divided into two broad functional categories, those that control intracellular regulatory circuitry and those that influence cell surface and extracellular functions.

 

The first category is further divided into four subcategories:

(1) genes that play a role in the responses of cells to external growth stimuli (i.e. genes that encode growth factors, cellular receptors, coupling proteins, and protein kinases that transduce information across the cytoplasm to the nucleus) and nuclear transcription factors that then increase or repress the expression of specific genes;

(2) genes involved in DNA replication and repair;

(3) genes involved in cell cycle control, including checkpoint functions; and

(4) genes that determine cell fate, i.e. cellular differentiation, senescence and programmed cell death (apoptosis).

 

Many of the oncogenes, for example ras, are in subcategory 1. Subcategory 2 includes the DNA excision and mismatch repair genes. Subcategory 3 includes the tumor suppressor genes Rb and p53. Recent studies on cyclins and cyclin-related genes and their abnormalities in cancer have rapidly expanded this subcategory (11,12). This subject is discussed in greater detail below. Subcategory 4 includes the bcl-2 family of proteins that regulate apoptosis.

 

This category is of considerable importance since it is now apparent that the increased proliferation of cancer cells reflects a disturbance in the balance between de novo cell replication and terminal differentiation, senescence and apoptosis, rather than simply increased cell replication. The second category includes genes that influence how cells interact with the extracellular matrix and/or neighboring cells. This category includes various cell surface proteins, cell adhesion molecules, extracellular proteases and angiogenesis factors. Alterations in these genes are especially relevant to tumor cell invasion and metastasis.

View this table:

Table I.

Categories of genes targeted during multistage carcinogenesis

 

There are several caveats related to this classification scheme. Thus, some of the above-mentioned genes perform multiple functions that extend across these categories (i.e. p53); there is cross-talk between components in each category and between categories, and the biological effects of some of these genes are dependent upon the context of the specific cell type in which it is expressed, a theme which will be further developed later in this paper. Therefore, the classification scheme shown in Table I is an oversimplification, nevertheless it may provide a useful framework and highlights the diverse functions that are perturbed during carcinogenesis.

 

 

 

 

Abnormalities in cell cycle control proteins in cancer

Subcategory 3 in Table I represents a recent set of oncogenes and tumor suppressor genes, discovered as a result of the recent elucidation of the specific proteins that normally regulate the cell cycle in a variety of eukaryotic cells. As shown in Figure 1, the orderly progression of dividing mammalian cells through the G1, S, G2 and M phases of the cell cycle is governed by a series of proteins called cyclins, which exert their effects by binding to and activating a series of specific cyclin-dependent kinases (CDKs). This process is further modulated by the phosphorylation and dephosphorylation of CDK proteins by specific protein kinases and phosphatases and by a series of specific CDK inhibitor proteins (CDIs), including p16INK4a, p21Waf1 and p27Kip1 (Figure 1B) (11,12).

View larger version:

Fig. 1.

  • Simplified model of the cell cycle indicating the G0 phase of non-dividing cells, the G1 phase when cells enter the cell cycle and prepare for DNA synthesis, which occurs in the S phase, and the G2 and M phases in which cells prepare for and then undergo mitosis. The major cyclin–CDK complexes acting at each phase of the cell cycle are also shown.

 

  • There are two checkpoints during the cell cycle: the G1/S checkpoint (also termed restriction point) at which Rb and p53 exert inhibition on the G1/S transition, and the G2/M checkpoint at which cells are also prevented from progressing through the cell cycle until errors are corrected. (For additional details see text and refs 11,12.) (B) Multiple mechanisms regulate cyclin/CDK activities. This figure indicates the regulation of cyclin D1–CDK4. Phosphorylation on a conserved Thr (Thr-172 in CDK4) and dephosphorylation on Thr-14 and Tyr-15 are required for activation of the complex. A group of CDIs designated p21CIP1, p27Kip1, p16INK4, and other related proteins bind to the cyclin–CDK complex and inhibit kinase activity. Various external factors acting through the CDIs can cause cell cycle arrest.

 

  • Phosphorylation of the Rb protein by the active cyclin D–CDK4 complex can release E2F transcription factors, which enhances the G1–S transition and the onset of DNA synthesis in the S phase. p27Kip1 plays a critical role by binding to and inhibiting cyclin E/CDK2. (For additional details see text and refs 11,12.)

 

In recent years it has become apparent that carcinogenesis is frequently associated with mutations or abnormalities in the expression of various cyclins, CDKs and CDIs, in several types of human cancers (for review see refs 11,12). Thus, the cyclin D1 gene, which acts at the mid-portion of the G1–S transition, is often overexpressed in human breast, colon and squamous carcinomas, and several other types of cancer, and the cyclin E gene, which acts in late G1 is also overexpressed and dysregulated in a variety of human cancers (11,12).

 

Indeed, increased expression of cyclin D1 is one of the most frequent abnormalities in human cancer since it occurs in ~60% of breast cancers, 40% of colorectal cancers, 40% of squamous carcinomas of the head and neck and 20% of prostate cancers (10–13).

 

Furthermore, increased expression of cyclin D1 can be an early event in carcinogenesis, since it is also seen in precursor lesions of the colon, esophagous and breast (14,15 and unpublished data). It may, therefore, be a useful biomarker in molecular epidemiology and chemoprevention studies. It is of interest that the APC/β-catenin pathway regulates the expression of cyclin D1 (16,17), which may explain why cyclin D1 is often overexpressed in colorectal cancers (11,12,14). Amplification and overexpression of CDK4 is also seen in human cancers (11,12). Abnormalities in the expression of CDIs and in the retinoblastoma (Rb) gene, which plays a crucial role in controlling the G1–S transition, are described below.

 

The proteins CDC25A and CDC25B, which are phosphatases that activate cyclin/CDK complexes, are frequently overexpressed in human breast cancers (18), non-small-cell cancers (19) and head and neck cancers (20). Using an MMTV-CDC25B construct we have developed transgenic mice that overexpress CDC25B in the mammary gland and found that this increases susceptibility to induction of mammary tumors by dimethylbenz[a]anthracene (21), thus demonstating a synergistic interaction between a carcinogen and a cell cycle control protein in carcinogenesis.

 

In mechanistic studies we demonstrated that overexpression of cyclin D1 can play a critical role in carcinogenesis since introduction of an antisense cDNA to cyclin D1 into esophageal or colon cancer cells reverts their phenotype towards normal and inhibits tumorigenicity (22,23). This finding has been extended by other investigators, to pancreatic (24) and squamous carcinomas (25). Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased sensitivity to chemotherapeutic agents (24).

 

We also found that overexpression of cyclin D1 can enhance the process of gene amplification (26), and this finding has been confirmed by others (27). Therefore, increased expression of cyclin D1 could enhance the process of tumor progression during multistage carcinogenesis, by causing genomic instability. Taken together, these findings suggest that drugs that inhibit cyclin D1 expression or activity, or the activity of CDK4, may be useful in cancer chemoprevention or treatment (10,22,23).

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Paradoxical overexpression of tumor suppressor genes

Studies on p27Kip1

 

As discussed above, according to the current paradigm carcinogenesis is associated with activation of oncogenes and decreased expression of tumor suppressor genes. Therefore, we were surprised to find relatively high levels of expression of the protein p27Kip1 in a series of human esophageal cancer cell lines (28). This protein inhibits cell cycle progression by binding to and inhibiting the activities of cyclin/CDK complexes (Figure 1B), especially cyclin E/CDK2 and, therefore, it is a putative tumor suppressor gene (29).

 

In addition, genetically engineered mice with reduced expression of p27Kip1 display increased sensitivity to carcinogen-induced tumor formation, even if only one allele is inactivated (30). We found that several human colon and breast cancer cell lines also express high levels of p27K1p1, even during exponential growth, but this protein is expressed at low levels in three normal human mammary cell lines (31–35).

 

Furthermore, we found that whereas in normal mammary epithelial cells the level of the p27Kip1 protein varies during the cell cycle, in breast cancer cell lines the level can remain high throughout the cell cycle (34). The high level of p27Kip1 in these cancer cells is not simply an artefact of cell culture, since we and other investigators have found that p27Kip1 is also expressed at relatively high levels in a subset of primary human breast and colon cancers (34–38). It is also overexpressed in small-cell carcinomas of the lung, despite their high degree of malignancy (39).

 

The increased expression of p27Kip1 in cancer cells seems paradoxical, especially because mutations in this gene have not been found or are extremely rare in various cancers (29). A possible explanation for the paradoxical increase in p27Kip1 in some cancer cells is that they have become refractory to the inhibitory effects of this protein. To address this question, we transfected the MCF7 human breast cancer cell line and the MCF10F human non-tumorigenic mammary epithelial cell line with a vector containing the p27Kip1 cDNA to obtain derivatives that express increased levels of p27Kip1 (40).

 

The increased expression of p27Kip1 in derivatives of both of these cell lines was associated with lengthening of the G1 phase, an increase in the doubling time, a decreased saturation density and a decreased plating efficiency. In the MCF7 cells, anchorage-independent growth and in vivo tumorigenicity were also suppressed. These effects were associated with decreased cyclin E-associated in vitro kinase activity, in both cell lines. Thus, breast cancer cells are still responsive to p27Kip1-mediated inhibition of cell growth despite the high basal level of this protein. These results suggest that therapeutic strategies that further increase the level of expression of p27Kip1 or mimic its activity might be useful in cancer therapy (40).

 

Curiously, we found that cancer cell lines and tumors that had high levels of p27Kip1 also frequently had high levels of cyclin D1 (28, 31–35). Furthermore, ectopic overexpression of cyclin D1 in esophageal (28) or mammary epithelial cell lines (31) was associated with increased expression of p27Kip1, and when an antisense cyclin D1 cDNA was introduced into either esophageal or colon cancer cells to reduce the expression of cyclin D1, this led to reduced levels of the p27Kip1 protein (22,23 and unpublished data). We also found that overexpression of cyclin E in mammary epithelial cells is associated with increased expression of p27Kip1 (33,41).

 

Taken together, these findings suggest the existence of a feedback loop between cyclin D1 or cyclin E and p27Kip1, the purpose of which is to maintain a homeostatic balance between positive and negative regulators of the G1–S transition in the cell cycle (Figure 2).

 

The increased levels of p27Kip1 in cancer cells might protect these cells from potentially toxic effects of increased expression of cyclin D1 and or cyclin E (10,29). This regulation of p27Kip1 appears to occur at a post- translational level which is consistent with the fact that the regulation of its expression is usually regulated at this level by a ubiquitin-protesome mediated mechanism (29). There is evidence that one mechanism by which cancer cells are protected from the inhibitory effects of p27Kip1 is to sequester this protein in the cytoplasm to prevent it from inhibiting cyclin E/CDK2 in the nucleus. It should be mentioned that at low levels of expression p27Kip1 enhances the formation of cyclin–CDK complexes by acting as an assembly factor (29).

View larger version:

Fig. 2.

Schematic diagram indicating that cyclin D1 and cyclin E, when bound to CDKs, stimulate the G1–S transition of the cell cycle. At elevated levels they also can induce (through unknown mechanisms) an increase in cellular levels of the p27Kip1 protein, thus providing feedback inhibition of the activities of these cyclins.

 

Although, as discussed above, a subset of human cancers display relatively high levels of the p27Kip1 protein, including esophageal, breast, colon and small-cell lung cancers, recent studies indicate that another subset of human cancers displays decreased expression of this protein, and that this decrease is associated with high grade (poorly differentiated) tumors and an unfavorable prognosis. This association is remarkable since it has now been seen in a variety of human cancers including carcinomas of the breast, colon, stomach, prostate and oral cavity; as well as non-small cell lung carcinomas, gliomas, endocrine tumors and lymphomas (for review see ref. 29).

 

 

Because we found a correlation between the subset of colon cancers with high levels of p27Kip1 with well and moderately differentiated carcinomas (35) we wondered if p27Kip1 played a role in the differentiation of these cancers. Therefore, we examined the effects of stably overexpressing high levels of p27Kip1 in the human colon cancer cell line HT29, which can be induced to undergo differentiation in response to treatment with sodium butyrate (42). We found that the p27Kip1 overexpressor clones displayed an increase in the amount of the p27Kip1 protein in cyclin E/CDK2 immunoprecipitates and a corresponding decrease in cyclin E-associated kinase activity, when compared with vector control clones, providing evidence that the overexpressed protein was functional. Clones with a high level of p27Kip1 displayed partial growth inhibition in monolayer culture and a decrease in plating efficiency, even though they expressed increased levels of the cyclin D1 protein.

 

Using alkaline phosphatase expression as a marker, we found that the p27Kip1 overexpressor clones displayed a 2–3-fold increase in sensitivity to induction of differentiation by 2 mM sodium butyrate.

 

In contrast with these results, derivatives of HT29 cells that stably overexpressed p21Cip1/Waf1 displayed decreased sensitivity to the induction of differentiation (42). These results may explain why decreased levels of p27Kip1 in certain human cancers are associated with high grade tumors.

 

They also provide further evidence that therapeutic strategies that cause an increase in the level of p27Kip1 may be useful in cancer therapy. Since there already exist several agents that can increase the expression of p27Kip1 in specific cell types, including TGFβ, IFN-β, IFN-γ, cAMP agonists and rapamycin (29), in specific cell systems, this approach may be clinically feasible. Furthermore, adenoviral p27Kip1 gene transfer can induce apoptosis in several types of cancer cell lines (for review see ref. 29).

 

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Paradoxical increase in the Rb protein in colorectal cancer

 

The protein encoded by the Rb gene, pRb, normally plays a key role as a negative regulator of the G1–S transition in the cell cycle by binding the transcription factor E2F and preventing it from activating the transcription of genes required for the S phase (11,12).

 

The Rb gene is inactivated in a variety of human cancers, but in colorectal carcinomas there is frequently increased expression of this gene (43,44). This is paradoxical in view of the known role of Rb as a tumor suppressor gene. In a recent study we compared the levels of expression of pRb in normal human colorectal mucosa, adenomatous polyps, and carcinomas by immunohistochemistry (44).

 

We found that there was a progressive increase in the expression of pRb during the multistage process of colon carcinogenesis. Thus, during the transition from normal mucosa to adenomatous polyps to carcinomas there was a progressive increase in pRb expression.

 

In vitro studies were also done to examine the phenotypic effects of an antisense oligodeoxynucleotide (AS-Rb) targeted to Rb mRNA in the HCT116 colon carcinoma cell line that expresses a relatively high level of pRb (44). Treatment of HC116 cells with AS-Rb decreased the level of pRb by ~70% and also decreased the levels of the cyclin D1 protein and cyclin D1-associated kinase activity.

 

 

This finding is consistent with other evidence of the existence of a feedback regulatory loop between Rb and cyclin D1 (44,45). A striking finding was that AS-Rb inhibited the growth of HCT116 cells and induced apoptosis. Reporter assays indicated an ~17-fold increase in E2F activity. Furthermore, we could mimic the growth-inhibitory and apoptosis-inducing effects of AS-Rb by simply ectopically overexpressing E2F in HCT116 cells. These findings suggest that the increased expression of pRb in colorectal carcinoma cells may provide a homeostatic mechanism that protects them from growth inhibition and apoptosis, perhaps by counterbalancing the potentially toxic effects of excessive E2F.

 

There is, indeed, evidence that the majority of colon tumors have high E2F activity (46). This could reflect the effects of activating mutations in the k-ras oncogene, increased expression of cyclin D1, or other factors that affect E2F levels and/or activity.

 

We found that transfection of our As-Rb into WI38 human lung fibroblasts stimulated rather then inhibited growth (44), which is consistent with previous evidence that in several cell types pRb acts as a growth inhibitor.

 

The seemingly paradoxical effects found in colon cancer are not unique since there is evidence that subsets of human bladder and breast cancers and leukemias can also display increased expression of pRb, and that pRb can protect bladder cancer cells, osteosarcoma cells and hepatic carcinoma cells from apoptosis induced by various agents (44,47).

 

It is also apparent that, whereas E2F can act as an oncogene in some cell systems, in others it can induce apoptosis (44,48). Thus, the effects of altered expression of pRb and E2F, like that of numerous other oncogenes or tumor suppressor genes, is highly context dependent. This subject is discussed in greater detail below.

 

The mechanism by which pRb expression is upregulated in some human cancers is not known. It has been suggested that in some cases this may be due to loss of expression of p16INK4a, since there appears to be a homeostatic feedback regulatory loop between pRb and p16INK4a (44,49,50).

 

Paradoxical increases in other inhibitors of the cell cycle

 

As described above, the CDI p27Kip1 is often expressed at relatively high levels in human cancer cells. High levels of expression of another CDI, p21WAF1, have also been seen in some human tumors, including glial tumors (51), non-small cell lung carcinomas (52), leiomyosarcomas (53) and breast carcinomas (54). Curiously, in breast cancers high p21WAF1 expression was associated with high tumor grade and a poor prognosis (54).

 

In pancreatic cancer cells there was a correlation between high expression of cyclin D1 and p21WAF1 (55). In addition, cyclin D1 can induce increased expression of p21WAF1 through an E2F mechanism (56). This provides another example of a homeostatic feedback mechanism that is retained in many tumors.

 

Human tumors often display loss of expression of the CDI and tumor suppressor p16INK4a, either because of mutations in the gene or transcriptional silencing due to hypermethylation (57). However, recent studies indicate that subsets of gastric and colon cancer can display increased expression of the p16INK4a protein (H.Yamamoto, personal communication). High levels of expression of p16INK4 have also been seen in human neuroblastoma cell lines (58).

 

 

The significance of this finding remains to be determined. It is of interest that loss of expression of pRb is often associated with increased expression of p16INK4a, suggesting the existence of a homeostatic feedback loop between these two proteins, as discussed above (44,49,50).

Overview: the role of homeostatsis in carcinogenesis, when Yin meets Yang

 

The above studies indicate that in several types of human cancer there can be an increase in the expression of the tumor suppressor genes p27Kip1, p21WAF1, p16INK4 or Rb. As discussed above, this may reflect, at least in part, the existence of homeostatic feedback loops in cell circuitry that maintain an appropriate balance between growth promoting and growth inhibitory factors. Figure 3 lists additional examples of what appear to be homeostatic feedback loops in pathways of signed transduction, i.e. examples of a `Yin/Yang’ phenomenon in which a growth enhancing factor induces a growth inhibitory factor or visa versa.

 

In addition, it is now apparent that the biologic effects of oncogenes and tumor suppressor genes are highly context dependent (10,60). Examples include the ability of an activated ras gene or the transcription factor E2F to either enhance apoptosis or induce malignant cell transformation, depending on the cell system (60). Furthermore, the biologic effects of several oncogenes depend on their level of expression. For example, moderate overexpression of cyclin D1 can enhance cell growth but a high level of expression can be toxic to cells (61). The biologic effects of various protein kinases are also dependent on the cell context and their level of expression. We encountered this phenomenon in our studies on the biologic effects of specific isoforms of protein kinase C (62) and their roles in signal transduction (63).

View larger version:

Fig. 3.

Examples in which a factor which enhances growth (Yang') leads to an increase in the expression of a factor that inhibits growth (Yin’) and vice versa. These effects are often cell type specific. For additional details see text and related references. For the effect of p53 on cyclin D1 see Chen et al. (59).

 

Table I illustrates the remarkable diversity in function of the known oncogenes and tumor suppressor genes. It should also be emphasized that many of the respective proteins interact with each other in complex networks, rather than simple linear pathways, that display cross-talk and negative or positive feedback loops, analogous to electronic circuits (10,64–66), and the various pathways of signal transduction can be thought of as interconnecting modules' (66). Therefore, the accumulated effects of the multiple mutations in cancer cells leads to bizarre types of circuitry, i.e. circuits which were not present in the original parental cell, or in any other normal cell type. As a consequence, certain proteins in a cancer cell function within a novel context, since they are linked, either upstream or downstream, to proteins they are not linked to in normal cells. For similar reasons, an increase, decrease or loss of a given protein in a tumor cell might have a differentmeaning’ to a cancer cell than to a normal cell, and the experimental re-introduction of a deleted protein into a cancer cell might exert effects different from those that occur when the same protein is present and expressed in normal cells.

 

This formulation can help to explain certain otherwise unexpected experimental results, and may also provide reason for optimism in the design of cancer-specific therapeutic agents. It has always seemed puzzling why the introduction of a single wild-type tumor suppressor gene, like p53, Rb or APC, into malignant tumor cells that carry multiple mutations can profoundly inhibit growth or induce apoptosis and/or inhibit tumorigenicity (67–69).

 

If, according to the current paradigm, these cells originally evolved into a malignant tumor through the stepwise acquisition of several mutations, then the correction of one of these mutations should have only a small inhibitory effect. We believe that these results reflect the altered or bizarre circuitry of cancer cells, and refer to this phenomenon as `gene hypersensitivity’ (10).

 

In our studies on cyclin D1 we encountered another effect which also seemed puzzling. As mentioned above, we found that stable expression of an antisense cyclin D1 cDNA in a human esophageal cancer cell line, which carries an amplified cyclin D1 gene and expresses high levels of cyclin D1, depressed cyclin D1 expression, and this was associated with a dramatic reversion of the cells towards a more normal phenotype (22).

 

Nevertheless, the residual level of cyclin D1 protein expression in the reverted cells was considerably higher than in other rapidly growing and highly tumorigenic cells in which cyclin D1 was not amplified or overexpressed. These findings suggest that during the original evolution of these cancer cells they became `addicted’ to cyclin D1 (10) and, therefore, require high levels of this protein to maintain their cancer phenotype. A possible explanation is that these cancer cells express relatively high levels of proteins that counteract the effects of cyclin D1, for example Rb or one of the CDIs.

 

Thus, even only a partial decrease in cyclin D1 in these cells would alter the stoichiometry between it and the respective inhibitory proteins, thus resulting in net inhibition of cell growth (10). If this explanation is correct, then cancer cells that are addicted to cyclin D1 might be unusually susceptible to drugs that block the action of cyclin D1. This general model might also apply to other genes that are amplified and/or overexpressed, or constitutively activated, in cancer cells. Indeed, it has been shown that pancreatic cancer cells that carry a mutated and activated k-ras gene are more dependent on the function of the k-ras gene for growth than pancreatic cancer cells that do not carry this mutation (70).

 

 

 

 

Another example of gene addiction is the finding that erB-2 antisense oligonucleotides inhibit the proliferation of breast carcinomas cells with erB-2 amplification but have no specific effect on breast cancer lines that do not have amplification of erB-2 (71).

 

The bizarre circuitry of cancer cells and the phenomena of gene hypersensitivity and gene addition could be the long sought Achilles’ heal of cancer cells. Indeed, they might explain why tumor cells are often more susceptible to the induction of apoptosis than normal cells by some of the currently employed cancer chemotherapy agents.

 

The concept of homeostasis is pervasive in biologic systems and dates back to the 19th century physiologist Claude Bernard who emphasized the constancy of the `interior milieu’ of the body in the face of an ever-changing exterior environment. The term itself was first used by Walter B.Cannon in the 1930s who emphasized the role of the autonomic nervous system in maintaining steady states within the body (72). Subsequent studies of the endocrine system provided further examples. With the more recent elucidation of biochemical pathways of biosynthesis and energy metabolism and current studies on pathways of signal transduction, the concept of homeostasis has been extended to intracellular mechanisms.

 

It seems likely that the principal of homeostasis is also maintained during the process of multistage carcinogenesis, as discussed above. This seems reasonable since, despite its numerous abnormalities, the cancer cell must coordinate highly complex functions in order to survive and replicate. Therefore, the clonal evolution theory of cancer, proposed by Nowell (73), and the current paradigm of oncogenes and tumor suppressor genes (4), requires modification. The multistage process of carcinogenesis does not simply involve the step-wise activation of growth-promoting oncogenes and inactivation of growth inhibitory tumor suppressor genes.

 

The regulatory circuitry of the evolving population of tumor cells must adapt to the stochastic occurrence of these mutations, some of which might on their own inhibit growth or cause apoptosis. Presumably this occurs through homeostatic feedback mechanisms, like those described above, and/or cell selection, thus maintaining a homeostatic balance that favors optimal growth and viability. This concept could help to explain the long latent period in carcinogenesis and the complex and heterogenous phenotypes of cancer cells. It also has implications with respect to novel approaches to cancer chemoprevention and therapy, because of the bizarre circuitry that results from these alterations and the phenomena of gene hypersensitivity and gene addition, as discussed above.

 

 

The concept of cancer as a global disturbance of the network of regulatory circuitry within cells also has implications with respect to the limitations of the current approaches used for characterizing the genotypes and phenotypes of specific cancers. Currently, this is often done by analyzing a few genes, transcripts or proteins. The recent development of microarray methods (74) and proteomics markedly expands our ability to assess complex profiles of gene expression in cancer cells and, therefore, are major advances. However, these methods do not provide a dynamic view of the actual circuitry of cancer cells. A challenging future goal is to develop novel methods to assess this circuitry in living cells, and also to develop mathematical models (for example, see refs 64–66) for analyzing the complex networks and their interactions. Hopefully, the insights obtained from this new level of analysis will provide even more powerful approaches to cancer prevention and treatment.

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Acknowledgments

This paper is dedicated to Anthony Dipple, an outstanding leader in carcinogenesis research and wonderful colleague. I am indebted to several members of my laboratory who made invaluable contributions to this research. For brevity, I have often cited previous review articles or representative research papers. I apologize to other investigators for omitting numerous additional pertinent references. This research was supported by NIH Grant CA63467, AIBS grant DAMRD 17-94-J-4101, and awards from the National Foundation for Cancer Research, the T.J.Martell Foundation and the Alma Toorock Memorial for Cancer Research.

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Headache. Author manuscript; available in PMC 2013 Sep 4.

 

Published in final edited form as:

Headache. 2007 Jun; 47(6): 820–833.

doi:  10.1111/j.1526-4610.2006.00715.x

PMCID: PMC3761082

NIHMSID: NIHMS501945

 

The Cerebellum and Migraine

 

Maurice Vincent, MD, PhD and Nouchine Hadjikhani, MD

Author information Copyright and License information

 

The publisher’s final edited version of this article is available at Headache

See other articles in PMC that cite the published article.

 

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Abstract

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Clinical and pathophysiological evidences connect migraine and the cerebellum. Literature on documented cerebellar abnormalities in migraine, however, is relatively sparse. Cerebellar involvement may be observed in 4 types of migraines: in the widespread migraine with aura (MWA) and migraine without aura (MWoA) forms; in particular subtypes of migraine such as basilar-type migraine (BTM); and in the genetically driven autosomal dominant familial hemiplegic migraine (FHM) forms. Cerebellar dysfunction in migraineurs varies largely in severity, and may be subclinical. Purkinje cells express calcium channels that are related to the pathophysiology of both inherited forms of migraine and primary ataxias, mostly spinal cerebellar ataxia type 6 (SCA-6) and episodic ataxia type 2 (EA-2). Genetically driven ion channels dysfunction leads to hyperexcitability in the brain and cerebellum, possibly facilitating spreading depression waves in both locations. This review focuses on the cerebellar involvement in migraine, the relevant ataxias and their association with this primary headache, and discusses some of the pathophysiological processes putatively underlying these diseases.

Keywords: migraine, familial hemiplegic migraine, cerebellum, progressive ataxia, episodic ataxia

Migraine is a common disease that affects 10 to 12% of the population and is considered by the World Health Organization as one of the most disabling neurological disorders.1 Migraine attacks typically occur in varying intervals, each lasting 4 to 72 hours by definition. The unilateral, mostly side-shifting throbbing pain, located predominantly to the frontal parts of the cranium, may be intense enough to interrupt daily activity and worsens with physical activity. Nausea, vomiting, photo and phonophobia frequently accompany the annoying moderate to severe pain. A series of different neurological focal abnormalities named aura (from the Greek “breath,” gentle breeze), mostly visual in nature, but also sometimes sensory, motor, or dysphasic, may occur in close association with the pain, typically before the headache onset.2 The International Headache Society (IHS) classifies migraine headaches, among other less frequent subtypes, as migraine with aura (MWA), or migraine without aura (MWoA), according to the presence of aura symptoms.3

Pathophysiological Theories in Migraine

The mechanisms underlying migraine attacks remain fairly unknown, although accumulating data have demonstrated that this ailment is a primary brain disorder.4 A dispute whether migraine had either a nervous or a vascular origin, polarizing the 2 so-called “vascular” and “neuronal” theories, has been present for many years,5 but the central nervous system more probably seems be the ultimate source of migraine. The hitherto suitable vascular theory, which popularized the expression “vascular headache,” has been challenged by the information that aura and headache did not parallel changes in the vasculature.6 The possibility that abnormal brain hyperexcitability primarily originates migraine attacks is now widely accepted,7 and the disease threshold, at least partially, seems to be determined by genetic predisposition.8 The hyperexcitability has been confirmed by the relatively higher susceptibility of the migrainous cortex to phosphene induction secondary to transcranial magnetic stimulation.9 It seems, therefore, that the vascular responses take place because of primarily triggered events in the nervous system intimacy.

 

Spreading Depression

Spreading depression (SD) consists of a spreading wave of depolarization associated with a reduction of the cortical activity that lasts for minutes with a propagation speed of around 3 mm/min.

 

The expression “cortical spreading depression” (CSD) is widespread, but since this phenomenon is not exclusively cortical—it has been recorded in various tissues including the basal ganglia and thalamus,10,11 cerebellum,1215 tectum and olfactory bulb,12 retina,1622 and spinal cord23—we believe that “spreading depression” is a better denomination.

 

In 1945, Leão and Morrison suggested for the first time that SD could be related to the pathophysiology of migraine24 and Leão postulated that circulatory changes were in close connection with SD waves.25 SD compatible circulatory changes were subsequently found in migraineurs, making the possibility of SD being an important phenomenon in this disease even more attractive.6 SD is accompanied by an initial hyperperfusion, followed by prolonged and pronounced spreading hypoperfusion.26 The genetically hyperexcitable brain in migraine probably facilitates paroxysms of SD-like phenomena initiating each of them the cascade of events ultimately leading to the attacks. Functional imaging studies support the possibility of SD underlying migraine episodes.27 The trigeminovascular system comprised of the trigeminal fibers innervating meningeal and brain vessels is activated by SD,28 leading to plasma extravasation and vasodilatation (neurogenic inflammation) in the dura mater.29 The ability of triptans, a class of 5-HT1 agonists, to block neurogenic inflammation and neuropeptide release centrally, has supported the defense of its use as effective antimigraine agents.3032

 

The Cerebellum

 

Although Herophilus (335 to 280 B.C.) is usually cited for firstly recognizing the cerebellum (from Latin, “small brain”) as distinct from the brain, Aristotle did so before (“The history of animals” book I, part XVI, 350 B.C.). Galen (131 to 200 A.D.) called the vermis “the worm-like outgrowth,” Luigi Rolando (1773 to 1831) concluded the cerebellum was a motor structure, and Marie-Jean-Pierre Flourens (1794 to 1867) finally linked the cerebellum to coordination.33,34 The relatively simpler structure of the cerebellum is highly specific and uniform, with cells arranged in layers in the cerebellar cortex connected each other by a repetitive microcircuitry.35 The Purkinje cells are the source of cerebellar output. Therefore, malfunction in Purkinje cells severely impairs motor planning and coordination.

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CEREBELLAR DISORDERS IN COMMON MWA AND MWoA FORMS OF MIGRAINE

 

In spite of the fact that balance changes and vertigo have been recognized in migraine, only a few studies have specifically assessed cerebellar function between or during attacks. In migraine, stabilometry studies have revealed ictal and interictal balance abnormalities in treatment-free patients.36,37

 

Vestibulocerebellar function also seems compromised in migraineurs, with abnormal nystagmus in calorimetric testing and decrease in saccadic eye-movement accuracy.38 In addition, subclinical cerebellar impairment expressed as a lack of fine coordination has been shown interictally in migraineurs.39 Altogether, these findings indicate that migraine affects cerebellar function.39

 

It is not surprising that vestibular abnormalities may be detected in migraine patients, as about 2/3 of migraineurs are sensitive to motion and 1/4 may present with paroxysmal vertigo.40,41

Although a positive family history and previous motion sickness in childhood do not contribute to the diagnosis of MWoA, vestibular abnormalities are associated with this type of headache.42,43 Visual dysfunction may also impair coordination and probably impacts balance in migraine.44 Spatiotemporal function and motion processing are reportedly abnormal in migraineurs interictally45,46 and visual fields and contrast functions differ from controls.47

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BASILAR-TYPE MIGRAINE

Cerebellar dysfunction has been recognized in relation to special forms of migraine for many years. The expression “cerebellar migraine” was used in some German48,49 and Czech50 early publications.

 

In 1961, Bickerstaff described what he called “basilar artery migraine,”51 making the expression “basilar migraine” popular in neurology. According to the IHS, BTM is characterized by aura symptoms clearly originating from the brainstem and/or both hemispheres, without motor deficits.3 Symptoms may include dysarthria, vertigo, tinnitus, hypacusia, diplopia, visual symptoms, ataxia, decreased level of consciousness, and bilateral paresthesias.52 BTM has been considered more prevalent in adolescent girls with very positive family histories, but a recent analysis does not support BTM, which presents with ataxia in 5% of the cases, as a distinct migraine subform.53 The pathophysiology of BTM is not known. Circulatory changes and episodes of stroke putatively related to basilar-type migraine have been reported.54 Such infarcts have also been reported in the thalamus55 and the occipital areas.5658 Knowing the genetic mechanisms behind certain forms of migraine, scrutiny indicates that many migraine patients previously described according to their clinical pictures as “cerebellar migraine” or “basilar migraine,” probably carried one of the known ion channel related mutations. A mutation at the FHM2 locus at the ATP1A2 gene has been described in familial BTM without hemiplegia, suggesting a connection between BTM and hemiplegic migraine.59 BTM most probably represents a variation of MWA rather than another migraine subtype, as 95% of the BTM patients experience typical aura as in MWA.53

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FAMILIAL HEMIPLEGIC MIGRAINE AND THE CEREBELLUM-RELATED DISORDERS

FHM is an autosomal dominant disorder characterized by migraine attacks with hemiplegic aura. The diagnosis is based on the presence of aura including motor weakness and at least one first- or second-degree relative suffering from migraine with aura that presents with motor deficits.3 A multitude of associated symptoms may be present, including ataxia, seen in one-third of the families.60 Three types of FHM have been described so far: FHM-1 is consequent to mutations of the CACNA1A gene coding for a P/Q calcium channel;61 FHM-2 is due to the mutation of the ATP1A2 gene coding for the alpha2 subunit of the Na/K astrocytic ATPase;62,63 and FHM-3 follows a mutation of the SCN1A gene coding for a neuron voltage-gated sodium channel.64 The FHM phenotype includes hemiplegic migraine, seizure, prolonged coma, hyperthermia, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria.65

In FHM-1, the CACNA1A gene encodes the α1A (CAV2.1) subunit of the high voltage-gated P/Q type of calcium channel. This channel is expressed throughout the central nervous system, particularly in the cerebellar Purkinje cells, where it mediates depolarization-induced Ca2+ influx into presynaptic terminals and glutamate release.66,67 P/Q calcium channels play a pivotal role in neurotransmitter release68 and influence neuronal excitability.69 The consequences of different missense mutations in the CACNA1A gene may lead to gain-of-function of human P/Q-type calcium channels, although not all studies agree in this respect.70 New animal models may provide important insights in this field. A knockin mouse expressing the human R192Q pure FHM-1 mutation was genetically engineered and recently studied. This mouse shows gain-of-function P/Q Ca2+ channel function as evidenced by opening of calcium channels at lower levels of depolarization, lower threshold for SD and faster propagation speed.71 These findings open the possibility of SD-like phenomena in the cerebellum as a justification for cerebellar dysfunction in migraine patients. Human evidence confirming this hypothesis is however not yet available.

The mechanisms behind the neurological symptom complex linked to CACNA1A, ATP1A2, and SCN1A genes, respectively involved with FHM 1, 2, and 3, remain partially unclear. Noteworthy is the fact that, despite the type of ion channel involved, all mutations result in hyperexcitability and may be related to hemiplegic migraine, epilepsy, and/or ataxic disorders.

Cerebellar symptoms in FHM have been recognized in many families (Table). Such symptoms may be produced by lesion in the cerebellum itself or in structures with afferent or efferent cerebellar connections, such as the brainstem. Thus, the exact origin of symptoms such as nystagmus and ataxia in migraine patients cannot be definitely related to the cerebellum. On the other hand, the atrophy found in FMH and the calcium channel abnormalities in the cerebellum indicate that symptoms are probably cerebellar in nature.

table ft1table-wrap mode=article t1

Table

caption a4

Cerebellar Symptoms in Earlier FHM Descriptions

Around 20% of the hemiplegic migraine patients show permanent mild cerebellar deficits.72 Unconsciousness, fever, and confusion may occur associated with the hemiplegic attacks and ataxia, usually accompanied by cerebellar atrophy.73,74

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SPINOCEREBELAR AND EPISODIC ATAXIAS

The CACNA1A mutations are also involved with cerebellar diseases, namely episodic ataxia type 2 (EA-2) and spinocerebellar ataxia type 6 (SCA-6). Hereditary EAs are genetic conditions typically characterized by recurrent clumsiness triggered by exertion, stress, or fatigue with a favorable response to acetazolamide.75,76 Spinocerebellar ataxias (SCA) are genetic non-paroxysmal, moderate to severe ataxias of late onset characterized by progressive cerebellar degeneration leading to incoordination. Other cerebellar symptoms associated with spinal cord signs, such as motor deficit, as well as vibratory and proprioceptive sensory loss.75 The myriad of cerebellar symptoms include dysarthria, dysmetria, tremor, and nystagmus of various types.77

A series of EA mutations have been found so far,76,7880 and a complete loss of the P/Q function has been suggested to underlie the pathophysiology of EA-2.81 Different nomenclature in successive descriptions have confused the understanding of non-progressive ataxias.8284 SCA-6 has been associated with small expansions of a CAG repeat at the 3′ end of the CACNA1A gene, and point mutations are responsible for the allelic disorders related to EA-2.60,79,8587 The genetics behind these phenotypes, however, may vary.88 Regardless of the mutation type, hyperexcitability seem to stand behind all the different phenotypes. Interestingly, a mutation in the glutamate transporter excitatory aminoacid transporter 1 (EAAT1) is also related to episodic ataxia (EA), seizures, migraine, and alternating hemiplegia.89 EAAT1 is expressed particularly in the cerebellum and brain stem. The mutation in EAAT1 may lead to a reduced capacity for glutamate reuptake, increasing hyperexcitability. This reproduces the pathophysiological conditions present in channelopaties leading to FHM, episodic/progressive ataxias and coma after minor head trauma.

SCA-6 represents the form of progressive ataxia with closest relation to FHM pathophysiology, as this form of SCA is also linked to the CACNA1A gene.90,91 Different mutations have been linked to the phenotype of SCA-6, sometimes associated with FHM.92 There may be marked cerebellar atrophy on MR examination in these patients.93 Not only mutations occur at the same gene, but in 20% of FHM patients permanent cerebellar symptoms are present.94,95

The phenotypes of such disorders may vary between and within families.91,96 EA-2 patients may sometimes have non-hemiplegic migraine, which presents after the onset of the ataxic symptoms.97 Interictally, EA patients may present constant cerebellar symptoms and signs such as nystagmus and cerebellar atrophy. The migraine-progressive episodic ataxias symptoms interchange indicate that the cerebellar disorders related to channelopathies intermingle and may represent different aspects from the same abnormality. Mechanisms behind ataxias in migraine disorders most probably involve membrane dysfunction. Purkinje cells, where P/Q-type calcium channels are mostly expressed, fire according to intrinsic regular spontaneous pacemaking.98 This intrinsic pacemaking activity is irregular in P/Q-mutant Purkinje cells as well as in w-agatoxin IVA-blocked P/Q-type calcium channel in wild Purkinje cells. The defective P/Q calcium current decreases the function of calcium-activated potassium (KCa) channels, which are fundamental for the precision of the Purkinje cells intrinsic firing. EBIO, a channel activator that increases the affinity of KCa channels for calcium, recovers the regular firing in affected Purkinje cells.99 This makes the KCa channel a potential therapeutic target not only for EA-2, but also for related symptoms in migraine disorders.

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COMA, CEREBELLUM, AND MIGRAINE

One of the conditions associated with cerebellar dysfunction, FHM and the CACNA1A gene is fatal coma after mild head trauma.100102 Some mutations have been related to this phenotype. Patients carrying the T666M mutation in CACNA1A gene,103 but not exclusively as the chromosome 1 has also been implicated in this kind of abnormality104—may present coma following relatively mild head trauma, with brain edema and sometimes long-lasting coma.101103,105107 The S218L mutation was shown to produce particularly severe brain edema after trauma.108

As a hypothesis, the mechanisms leading to coma can be understood as follows: minor trauma, a relatively irrelevant depolarizing stimulus in healthy subjects, may elicit SD in patients with a particularly marked Cav2.1 channel gain of function, both in the brain and cerebellum. Further activation may then take place through a positive feedback leading to Cav2.1-dependent glutamate release, activation of NMDA receptors, de novo increase of extracelullar K+, glutamate release, and more NMDA receptor activation.109 SD may disrupt the blood–brain barrier by activating MMP-9, one of the proteases implicated in BBB opening,110 leading to brain edema and coma. Interestingly, the long-lasting edema and coma take place after a time interval following the trauma. This indicates that the process is not dependent on immediate neuronal impulses and neurotransmitters release, but on time consuming progressive changes. Moreover, the resulting pathophysiological state is a self-perpetuating process with a relatively slow recovery rate. Positive SD and calcium waves (see below) feedbacks in particularly excitable subjects would fit with these requirements. Transient global amnesia (TGA), a potentially SD related disorder,111 may also be induced by minor head trauma, just as coma in some patients with genetic forms of migraine where cerebellar abnormalities may be present.112

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THE ACETAZOLAMIDE EFFECT

Acetazolamide, a reversible inhibitor of the enzyme carbonic anhydrase, is a drug known for its benefit in EA-2.79,113,114 Acetazolamide-responsive episodic symptoms, typical of EA-2, have also been shown in SCA-6.115 The effect of acetazolamide in EAs was found in 1978 by chance, when patients received this drug after being erroneously diagnosed as periodic paralysis.114 Acetazolamide response has been described in FHM with associated ataxia74 and in migraineurs without cerebellar symptoms.116

Acetazolamide does not usually diminish the frequency or intensity of FHM, being mostly indicated for use in EA-2. However, there are 2 FHM reports with clear acetazolamide response.74,116 Formal trials using acetazolamide in migraine are few. In an open uncontrolled pilot study, the efficacy and tolerability of acetazolamide were addressed in 22 MWA patients. 68.2% reported a reduction of MA episodes higher than 50%.117 A randomized clinical trial was performed comparing 500 mg oral acetazolamide versus placebo in 53 IHS migraine patients (27 in the placebo group). This study had to be interrupted prematurely due to many side effects related withdrawals. So far, the authors did not find a difference between the active drug and placebo.118 Acetazolamide was also shown to interrupt aura status in 3 patients.119

The acetazolamide mechanism of action in episodic ataxia type 2 (EA-2) is still mysterious. It is interesting that topiramate, an effective antimigraine prophylactic agent, shares with acetazolamide the property of carbonic anhydrase inhibition.120 Besides, it was recently reported to suppress the susceptibility to cortical spreading depression in experimental animals.121 Acetazolamide induces metabolic acidosis. It is possible that this drug increases the extracelullar concentration of free protons in the brain tissue including the cerebellum.113 Since calcium channels are sensitive to pH changes, acetazolamide could restore normal function in mutant calcium channels through acidification. However, acetazolamide does not modify the channel properties through either pH-dependent or pH-independent mechanisms.122 Alternatively, since acetazolamide activate largeconductance KCa channels, which are in normal conditions exclusively activated in Purkinje cells by P/Q-type calcium channels, it is possible that this drug acts by restoring Purkinje cells pacemaking properties.99

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CEREBELLAR CIRCULATORY CHANGES

 

Circulatory changes may take place in the cerebellum during migraine attacks. Following sumatriptan administration, a vasoconstricting antimigraine agent, infarction has been described in the cerebellum, showing that this area was probably predisposed to ischemia as compared to other regions.123 Decreased perfusion and cerebellar symptoms, including dysarthria, ataxia, and dizziness have been described in migraine.124,125 Such circulatory changes can outlast the symptoms.125 Stroke in the posterior circulation has been reported in migraine54,123 including in children,126 mostly diagnosed as “basilar migraine.” The posterior circulation territory, particularly the cerebellum, shows significantly increased risk for infarct-like MRI findings compared to the remaining of the nervous system. The highest risk is in MWA with at least 1 attack per month, in the absence of stroke history.127 According to the CAMERA study, the percent of all these small, infarct-like lesions in the posterior circulation in MWA, MWoA, and controls were 81, 47, and 44%, respectively; the majority was in vascular border zones; and multiple posterior circulation lesions were identified exclusively among the migraine patients.128

 

The nature and pathophysiology of such infratentorial lesions are not known. Since the cerebellar circulation has relatively few anastomoses, it is prone to watershed infarcts.129 SD related reduction in rCBF could, theoretically, induce more infarcts in this territory as compared to areas where collateral circulation is available.

 

Although subjects do not present overt stroke symptoms, it is possible the subclinical cerebellar signs and symptoms in migraine36,38,39 are secondary to small infarcts in the posterior circulation.

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SPREADING DEPRESSION AND THE CEREBELLUM

 

Leão and Martins-Ferreira first published a 24 line note on SD in the cerebellum, quadrigeminal plate, and olfactory bulb12 and mentioned that the cerebellum is naturally resistant to SD. Fifková et al described SD in the rat cerebellum13 and Young wrote on the SD in the elasmobranch fish (Raja erinacea, Raja ocellata).14 As also pointed by Nicholson in 1984, reviewing cerebellar SD in different species,15 the cerebellum does not easily supports this phenomenon, unless some “conditioning” takes place.

 

This may happen by raising the extracelullar K+, removing most of the NaCl, or replacing the chloride with another anion. During SD, extracellular calcium concentration falls, reflecting Ca2+ influx with consequent intracellular Ca2+ overload, that may, if sufficiently high, promote cell death.130

 

Just as in the isolated retina and hippocampus, also in the turtle cerebellum SD occurs in the absence of blood flow, meaning that SD is not dependent on vascular or blood influence.15 If cerebellar SD is related to EA-2, pH changes alone may be not sufficient for explaining the acetazolamide effect. Alternatively, SD could occur in the cerebellum through facilitating mechanisms not involving pH reduction.

 

Other cortical self-propagating waves with potential implications in cerebellar diseases and migraine have been demonstrated. Spreading acidification and depression (SAD) has been observed in the rat cerebellar cortex following suprathreshold electrical stimulation.131 Substantial differences show that SAD and SD are not the same phenomenon.

 

SAD spreads at a greater rate of 50 to 110 m/s, continues for 1 to 2 minutes, is accompanied by a powerful suppression of the pre and postsynaptic responses, with a refractory period of 90 seconds. Differently from SD, SAD induces no extracellular DC shift, do not change blood vessels and has a shorter recovery period. Besides, the conditioning required for SD in the cerebellum is not required to elicit SAD. While SD propagates radially outwards from the initiating point, SAD spreads perpendicularly to an activated beam of parallel fibers, which makes its spreading pattern dependent on the cerebellar cortex neuronal architecture.

 

Pharmacologically, AMPA receptor blocking, which has little effect on SD, affects SAD, the opposite occurring with NMDA receptor blocking. SAD depends on extracellular Ca2+, while SD does not depend that strictly.132 SAD has been implicated in the pathophysiology of EA-1, where pathology is related to a Kv1.1 voltage-gated potassium channel abnormality,133 and is not likely to be involved with the cerebellar symptoms in migraine.

Astrocytes respond to glutamate with rapid calcium influx that propagate as waves from one cell to its neighbors.134

 

The so-called calcium waves (CW) constitute a signaling system that allows astrocytes to rapidly activate adjacent astrocytes and neurons, through gap junctions, and extracellular messengers,135,136 modulating synaptic transmission and neuronal activity.137 CWs are also triggered by neuronal activity138 and may be involved in blood flow regulation.

 

CWs have been implicated in cortical spreading depression. They were demonstrated in cell cultures and tissue preparations in different cell populations,139, 140 and precede SD waves in hippocampal cultures.141,142 Although these 2 forms of waves are related, SD does occur in calcium-free incubated hippocampal slices where CWs are abolished, demonstrating that the latter is not an obligatory requirement for the former.142 Since FHM and the related CACNA1A mutations diseases directly involve calcium fluxing, it is tempting to consider that CWs associated with SD might have a pathophysiological role in this context.143 The glutamate release induced by abnormal Cav2.1 channels in migraine could theoretically lead to not only SD, but also CW activation and further vasodilatation, contributing particularly to the phenotype of brain edema and coma following head trauma. The astrocytes’ role in brain water homeostasis regulation144 also supports this possibility.

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STRUCTURAL CHANGES IN THE CEREBELLUM AND MIGRAINE

Few studies have specifically addressed cerebellar structural changes in migraine. Dichgans et al found Magnetic Resonance Spectroscopy (1H-MRS) abnormalities in FHM-1 with reduced N-acetyl-aspartate (NAA), glutamate and elevated myo-inositol (mI) in the cerebellum, compatible with neuronal damage. Increased pH in the cerebrum and cerebellum, which normalized following acetazolamide treatment, as well as high lactate peak in half of the subjects has been reported in EA-2 patients.145 Autopsy studies have shown pathological abnormalities in SCA including mild atrophy of the cerebellar folia, reduced number of Purkinje cells especially in the vermis, swelling of the Purkinje cell axons, decrease in granular cells, reduced number of dendrites in the molecular layers of Purkinje cells, and cerebellar cortical degeneration with reduced thickness of the molecular layer.100, 146 In FHM, cerebellar vermis atrophy and cortical cerebellar degeneration accompanied with Bergman glia proliferation have been described.147

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FINAL REMARKS

Taken together, the data suggest that the cerebellum is implicated not only with FHM, but also with more typical migraine forms such as MWA and MWoA. The ionic and signaling changes present in migraine may affect also the cerebellum potentially leading to cerebellar dysfunction (Fig.). Cerebellar symptomatology, which does not depend on the presence of headache, may be episodic, suggesting an underlying transitory neuropathological change in the cerebellum such as SD; or present as a constant-progressive disorders. In this case, an increase in Ca2+ influx secondary to defective Ca2+ channels expressed by Purkinje cells would favor apoptosis, possibly in a cumulative, slowly progressive pattern. Alternatively, cumulative microvascular ischemia in watershed cerebellar areas secondary to successive migraine attacks could also impair cerebellar function with time in some cases. The pain may be produced by CGRP-containing sensory nerves activated by SD in the anterior circulation (trigeminal fibers) and/or posterior circulation (C2 fibers). Trigeminal fibers may also be partially activated by SD in some parts of the cerebellum as the rostral third of the basilar artery as well as the superior cerebellar artery are innervated by the trigeminal nerve.148,149

fig ft0fig mode=article f1

  Fig

caption a4

The brain and the cerebellum may share common pathophysiological mechanisms leading to different clinical pictures, which combine in diverse ways, largely varying in severity. Hyperexcitability, the pivotal abnormality in migraine, may be due to inherited

Knowledge on the genetic mechanisms leading to dysfunction in ion channels, ion pumps, and transporters has improved our understanding of migraine and related cerebellar disorders, although puzzling questions still remain. It is unclear how a multitude of phenotypes including minor trauma with edema and coma, fever, pleocytosis, hemiplegic migraine, and cerebellar ataxias, is related to a single mutation. The clinical picture in EA, for example, may vary to a great extent, such as from isolated mild ataxia to a constellation of symptoms suggestive of cerebellum, brainstem, and cortex dysfunction.150 This may indicate that phenotypic pleomorphism is a rule rather than an exception in these ailments. If an SD-like phenomenon underlies this group of diseases, it is likely that it may sometimes either not be clinically expressed, or manifest in different forms or degrees.

Cases reported as “basilar migraine,” “footballer’s migraine” or “cerebellar migraine” do not seem to constitute distinct entities. They may actually correspond to mere variations within the migraine channelopaty spectrum. As the molecular mechanisms implicated in migraine, ataxia, coma after minor trauma, and related disorders are better understood, it seems probable that clinical terms will be reviewed, and classifications will be established on a genetic-biochemical basis.

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Acknowledgments

The study was supported by a NIH grant 5PO1 NS 35611-09. MV is indebted to CAPES–Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Ministry of Education, Brazil; and Fulbright, USA, for a visiting professor scholarship. The authors acknowledge Professor Michael Moskowitz for his reviewing of this manuscript. Suggestions and comments by Dr. Alexandre Façanha daSilva and Cristina Granziera are appreciated.

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Abbreviations

   
IHS International Headache Society
MWA migraine with aura
MWoA migraine without aura
SD spreading depression
GABA gamma-aminobutyric acid
SCA spinal cerebellar ataxia
BTM basilar-type migraine
FHM familial hemiplegic migraine
EAAT1 excitatory aminoacid transporter 1
EA episodic ataxia
TGA transient global amnesia
SPECT single photon emission computed tomography
CW calcium waves

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Footnotes

back/fn-group

 

Conflict of Interest: None

 

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[Ann Neurol. 1999]

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[J Anat. 1987]

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[Stroke. 1989]

 

•   Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p.
[Ann Neurol. 1997]

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CMAJ September 11, 2007 vol. 177 no. 6 doi: 10.1503/cmaj.070001

  • Practice

 

A case of intermittent ataxia associated with migraine headaches

 

+

Author Affiliations

  • Yong Loo Lin School of Medicine, National University of Singapore, Department of Medicine, National University Hospital, Singapore

The case: A previously healthy 42-year-old woman had presented to our neurology service 1 year earlier with left-sided temporal headaches that she said typically lasted from a few hours to all day. They were associated with nausea but not with vomiting. Beginning at age 13 years, these headaches had occurred at a frequency of once a month to once every 2–3 months.

 

The woman did not experience visual auras, such as scintillation photopsias (flashes of light), migrating scotomata (patches of blurred or absent vision) or fortification spectra (wavy linear “zig-zag” patterns that resemble the battlements of a medieval fort).

 

She had no history of vertigo or seizures. The headaches tended to occur around the time of her menses. She rated the pain at 3 on a scale of 1–10 (10 being most severe), but she noted that on occasion the headaches could be severe enough to wake her from sleep and merit a pain rating of 8 or 9. Clinical examination was unremarkable during each of her visits.

 

Ten years earlier, atypical migraine had been diagnosed and treated symptomatically; no migraine prophylaxis had been given in view of her infrequent and mild headaches. Magnetic resonance imaging scans of the brain were unremarkable. The diagnosis of atypical migraine was not altered at this time.

One year after her initial visit to our neurology service, the patient was admitted to hospital because of unsteadiness of gait, gaze-evoked nystagmus and truncal ataxia (see video of typical episode, available online at www.cmaj.ca/cgi/content/full/177/6/565/DC1). She did not report experiencing headaches at the time. Her condition resolved spontaneously after about 18 hours, and findings on clinical examination were normal. She had no hearing loss or dysarthria and did not display any myokymia about the eyes, lips or fingers. She recalled experiencing similar mild attacks since the age of 25 that involved clumsiness and occasional falls and that lasted from a few hours to a day. These attacks were not associated with diplopia, hearing loss, weakness, choreiform movements, abnormal posturing, fatigable weakness, cognitive deficits, seizures, stiffness or myotonia. The attacks were not related to head position or change of posture. Her migraine headaches occurred both with and without episodes of ataxia. Similarly, ataxic episodes occurred without migraine headaches. An electroencephalogram appeared normal, as were the results of routine blood tests, including blood count, electrolyte levels and serum glucose level. The patient provided a detailed family history, describing intermittent clumsiness in her father and migraine headaches in 2 of 4 siblings.

A provisional diagnosis of episodic ataxia type 2 was made in view of the patient’s history of migraine, episodes of ataxia with normal examination between episodes and a strong family history.1,2 The patient responded to acetazolamide, 250 mg 3 times a day, but experienced relapses of ataxia once or twice a year when she did not take her medication. With amelioration of her ataxic episodes, she became bothered by her migraine headaches, which responded to prophylaxis with amitriptyline and indomethacin for analgesia. Sumatriptan was efficacious for more severe migraine headaches.

 

The patient underwent genetic counselling and testing. None of the known mutations that cause episodic ataxia was detected in exons 23, 26, 28, 29, 32 and 35 of the calcium-channel gene (CACNA1A) on chromosome 19p13, which codes for the main transmembrane component of the neuronal calcium channel.2

Ataxia can be progressive, stable or episodic and can occur with or without headaches (Box 1). Our patient had migraine headaches and episodes of ataxia, with normal clinical findings between attacks. Her ataxic episodes and migraines may have been distinct but coincidental clinical entities or manifestations of a single disease. A discussion of the differential diagnosis of recurrent and relapsing ataxia follows.

 

View larger version:

Box 1.

 

Episodic ataxias are characterized by spontaneous paroxysmal periods of ataxia that typically last from minutes to hours or days. Between episodes, the patient is normal, except for the presence of gaze-dependent or downbeat nystagmus.1,2 Migraine is associated with episodic ataxia in a variety of conditions, such as basilar type migraine; episodic ataxia types 1 and 2; episodic ataxia with paroxysmal choreoathetosis and spasticity; periodic vestibulocerebellar ataxia; and familial hemiplegic migraine.1 The clinical characteristics and distinguishing features of these conditions are summarized in Table 1.

 

View this table:

Table 1.

 

Our patient likely had episodic ataxia type 2 in view of her history of migraine, fairly long ataxic episodes (lasting minutes to hours), good clinical response to acetazolamide therapy and relevant family history. CACNA1A encodes the α-1A subunit of the voltage-dependent P/Q-type calcium channel, mainly expressed in the Purkinje cells of the cerebellum. Calcium channelopathy is thought to lead to alterations in intracellular pH, which alters the transmembrane potential. Acetazolamide is thought to normalize intracellular pH and thus restore Purkinje cell function.5 The patient’s negative genetic screen for episodic ataxia type 2 does not rule out the possibility that she has the condition, since we screened for only 6 of the mutations described to date. It is also possible, of course, that our patient carries a novel mutation in the CACNA1A gene or carries a mutation in some other gene. For example, a family whose members have the phenotype for episodic ataxia type 2 but who carry the genotype for episodic ataxia type 1 has been described.6

We ruled out basilar type migraine3 on the basis of the temporal dissociation between migrainous and ataxic episodes, as well as the patient’s favourable response to acetazolamide. We also excluded episodic ataxia with paroxysmal choreoathetosis and spasticity as well as familial hemiplegic migraine because of the absence of chorea, stiffness and hemiplegia during the headaches.

Channelopathies, such as paroxysmal kinesigenic dyskinesias, can be associated with migraine and can mimic episodic ataxias. Clinical examination during the attack (see online video, available at www.cmaj.ca/cgi/content/full/177/6/565/DC1) confirmed the presence of truncal ataxia rather than dyskinesia.

Migrainous headaches have also been reported to occur incidentally in patients who have ataxia because of other diseases, such as spinocerebellar ataxia type 6, celiac disease, antiphospholipid syndrome, paroxysmal psychosis and seizures. Similarly, they can occur in patients with cerebellar dysfunction or acutely from drugs (e.g., anticonvulsants) or toxins (e.g., alcohol).

Finally, ataxia may be seen intermittently as part of several recessively inherited diseases, such as Hartnup’s disease, pyruvate decarboxylase deficiency, Leigh’s disease and hereditary hyperammonemias. These conditions are usually associated with other signs, such as mental retardation, seizures and pyramidal dysfunction.

Episodic ataxia type 2 is treated with carbonic anhydrase inhibitors, such as acetazolamide, as well as migraine prophylaxis and therapy with analgesics. Magnetic resonance spectroscopy studies have demonstrated an increase in cerebellar pH in affected patients, which returns to normal on consumption of acetazolamide. The disease runs a relatively benign course, although progression to severe persistent cerebellar ataxia has been described in some cases.2 Our patient has remained well 6 years after initiation of therapy.

 

 

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Footnotes

  • See an online video showing an episode of moderately severe truncal ataxia (available at cmaj.ca/cgi/content/full/177/6/565/DC1). The patient did not have a migraine headache during this episode. This article has been peer reviewed.
Acknowledgements: We thank Soh-Eng Chew and Professor Jean-Marc Burgunder for performing the genetic analysis of the CACNA1A gene mutations. 
Competing interests: None declared.

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REFERENCES

  • ↵ Gordon N. Episodic ataxia and channelopathies. Brain Dev 1998;20:9-13. CrossRefMedline
  • ↵ Kullmann DM. The neuronal channelopathies. Brain 2002;125(pt 6):1177-95. Abstract/FREE Full Text
  • ↵ Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 2nd edition. Cephalalgia 2004;24(Suppl 1):S9-160.
  1. Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005;4:2-6. Medline
  • ↵ Harno H, Hirvonen T, Kaunisto MA, et al. Acetazolamide improves neurotological abnormalities in a family with episodic ataxia type 2 (EA-2). J Neurol 2004;251:232-4. CrossRefMedline
  • ↵ Lee H, Wang H, Jen JC, et al. A novel mutation in KCNA1 causes episodic ataxia without myokymia. Hum Mutat 2004;24:536. Medline
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