Protein That Controls Hair Growth Also Keeps Stem Cells Slumbering.

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STEM CELLS HAIR GROWTH DIVISION

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A protein involved in hair growth also keeps the skin’s stem cells from proliferating. This research raises questions about what stem cells need in order to maintain their ability to regenerate tissues — questions that may be key in developing treatments for patients with thinning hair.

Like fine china and crystal, which tend to be used sparingly, stem cells divide infrequently. It was thought they did so to protect themselves from unnecessary wear and tear. But now new research from Rockefeller University has unveiled the protein that puts the brakes on stem cell division and shows that stem cells may not need such guarded protection to maintain their potency.

This research, to be published in the January 25 issue of Cell, raises questions about what stem cells need in order to maintain their ability to regenerate tissue. It may also be key in developing new treatments for thinning hair.

The impetus for the work began five years ago when Elaine Fuchs, head of the Laboratory of Mammalian Cell Biology and Development, and several researchers in her lab discovered that the protein NFATc1 was one of only a few that are highly expressed within the stem cell compartment of the hair follicle. Clinical research, meanwhile, showed that a particular immunosuppressant that inhibits NFATc1, a drug called cyclosporine A, has a rather unsightly side effect: excessive hair growth.

Fuchs and Valerie Horsley, a postdoc in her lab, realized that there was a connection between the drug’s side effect and the abundance of NFATc1 within the hair follicle’s stem cell compartment — the bulge. The mice they treated with the drug grew fur at a much faster rate than mice they did not treat. The researchers then showed that this excessive hair growth was due to increased stem cell activity within the bulge, a process that cranked up the production of hair. Specifically, the hair cycle shifted gears from its resting phase, when stem cells slumber, to its growth phase, when stem cells proliferate.

To maintain their multipotent properties, though, it appears that these stem cells hardly needed much “rest” at all. These findings came as a surprise to the researchers, who, like their colleagues, had believed that stem cells proliferating infrequently protected them from depletion or mutations that would lead to hair loss. “It seems like the resting phase isn’t as necessary as was once thought,” says Horsley. “Even though these stem cells are highly proliferative, they still maintain their stem cell character.”

Using genetically engineered mice bred by colleagues at Harvard Medical School, Horsley and Fuchs then further explored what happens when skin stem cells lack NFATc1. They found that these mice looked exactly like the hairy mice that were treated with cyclosporine A: The loss of NFATc1 didn’t stop the hair cycle, but rather shortened the resting phase and prompted precocious entry to the growth state.

In probing the underlying mechanisms mediating this process, Horsley and Fuchs discovered that NFATc1, a transcription factor, blocks the expression of a gene that provides the cell cycle with “go ahead” signals at certain checkpoints. By blocking these signals, NFATc1 prevents the stem cells from dividing, preventing unnecessary wear and tear. These same cells, if treated with cyclosporine A, show a rapid loss of the transcription factor, an effect that turns the light green at these checkpoints.

For those with thinning hair, this research may hold promise. As people age, the resting phase of the hair cycle gets longer and longer such that the stem cells proliferate less frequently and hair does not grow at the rate it once did. “If we could use a local and more specific inhibitor of NFATc1 than cyclosporine A to stimulate these stem cells, which are just sitting there during an extended resting phase, we might be able to promote new hair growth,” says Fuchs, who is Rebecca C. Lancefield Professor at Rockefeller and an investigator at the Howard Hughes Medical Institute. “In a sense, by blocking NFATc1 activity in our older mice, their hair follicles were brought back to what appeared to be a more youthful state.”

So far, these proliferating stem cells lacking NFATc1 have not led to increased tumor formation, which is often a dangerous byproduct of triggering stem cells into action. “This is the first case where we have been able to activate the hair cycle without accompanying signs of tumorigenesis,” says Fuchs. “If we can control the activation process of follicle stem cells without promoting tumorigenesis, then this would be a big move in the right direction.”

This research was supported in part by the National Institutes of Health, American Society for Clinical Investigation and the Damon Runyon Cancer Research Foundation. Fuchs is a faculty member in Rockefeller’s Center for Clinical and Translational Science, which is supported by the NIH’s Clinical and Translational Science Award (CTSA) program.

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Link:  http://www.newswise.com/articles/view/537156/

Side effects are constant companions of chemotherapy since the day of its discovery. Though modern research has managed to curb side effects to some extent, moments of worries are still there. Sachin Jagdale explores the issue.

Side line the side effects.

Side effects are constant companions of chemotherapy since the day of its discovery. Though modern research has managed to curb side effects to some extent, moments of worries are still there. Sachin Jagdale explores the issue

Imagine being cured of cancer only to discover that you have become permanently infertile. Or you have conquered cancer at the cost of your kidneys and you will require dialysis throughout life. What will life be if the cost of curing cancer is getting a permanent hearing impairment? These are rare side effects of chemotherapy, but are extremely disturbing.

Chemotherapy is an effective option to treat cancer because it interferes with rapidly dividing cells. However, the agony is that chemotherapy cannot distinguish between the ‘good guys’ (normal cells) and the ‘bad guys’ (the cancer cells), both of which are rapidly dividing cells. Thus ever since the use of the first chemotherapy agents like nitrogen mustards and folic acid antagonist drugs in the 1940s, chemotherapy has extracted a heavy price. In fact oncologists have to accept this bitter fact and admit that some times the side effects of chemotherapy kill the patient than the cancer does. “It may be an immediate anaphylactic reaction or neutropenic related severe infection,” says Dr Ganapathi Bhat, Honorary consultant, Medical Oncologist and Stem Cell Physician, Jaslok Hospital and Research Center, Mumbai.

Dr Ganapathi Bhat
Honorary Consultant, Medical Oncologist and Stem Cell Physician
Jaslok Hospital and Research Center, Mumbai

There are various guidelines to be followed while using chemotherapy. Bhat says, “Cytotoxic agents should not be prescribed by physicians inexperienced in their use. Dosages are modified according to the curability of the tumour and established guidelines for each drug or regimen. Chemotherapy is generally postponed if the patient has an infection of any type, persistent toxicity from previous treatments, or significant debility from cancer (Karnofsky’s scale performance status less than 50 percent).”

Dr Avinash Deo
Medical Oncologist-Hemato oncologist, Asian Institute of Oncology
S L Raheja Hospital, Mumbai

The seriousness of the side effects has led to the practice of oncologists preferring to have extensive counseling sessions with the patients and their families before the start of the treatment, to make them aware of and prepare them for the possible side effects of chemotherapy. Since chemotherapy remains the most trusted way of treating cancer, patients hardly see any other alternative to deal with the disease. Dr Avinash Deo, Medical oncologist-Hemato oncologist, Asian Institute of Oncology, S L Raheja Hospital, Mumbai, echoes Bhat’s opinion on the side effects of chemotherapy. Deo opines, “Chemotherapy is the only proven therapy for cancer that has spread. Unfortunately chemotherapy has life threatening adverse effects. Chemotherapy and antibiotics kill by exploiting differences between the offending cell (bacteria or cancer cell) and the human cell. The cancer cell is a human cell and a few normal cells do get killed resulting in side effects.”

Unified efforts

Deo also offers a ray of hope, saying that almost all side effects of chemotherapy are reversible. What is more heartening is the possibility that an expert oncologist may even be able to minimises the side effects of chemotherapy by appropriate scheduling of chemotherapy sessions.

Ultimately, it requires the unified efforts of both doctor and pharma companies to alleviate the woes of cancer patients. The skill of doctors is to treat patients with minimal damage to his body while it is the duty of pharma companies to try their best to make drugs with less possible toxicity. Deo says, “Attempts to overcome toxicity of therapy fall into two general categories. The first is development of drugs that can counter adverse effects. Examples of this are drugs to counter nausea and vomiting (Ondansetron, Granisetron, Palonosetron, Aprepitant) and decreased blood formation (filgrastim, erythropoietin). The other approach is to develop drugs free of toxicity.”

There are many national and international pharma companies that produce chemotherapeutic drugs. There are many critics as well who criticise pharma companies for producing toxic drugs. A sample quote posted on the web by an eminent European oncologist Dr Glen Warner reveals the intensity of the debate on this subject; “We have a multi-billion dollar industry that is killing people, right and left, just for financial gain. Their idea of research is to see whether two doses of this poison is better than three doses of that poison.”

However, despite all negative criticism, companies like Glenmark Pharmaceuticals are genuinely focusing efforts to minimise toxicity of their chemotherapy drugs. Dr Akhilesh Sharma, MD (Bom), Vice President-Medical Services, Glenmark, says, “Globally a lot of research work has been directed towards the development of newer, safer and targeted therapies for better efficacy and safety profile. Research work at Glenmark is directed towards development of more targeted therapies for the reduction of toxicity by chemotherapeutic drugs.” He adds, “NK1 receptor antagonists are effective against delayed chemotherapy induced nausea and vomiting (CINV) besides having a role in acute CINV. Glenmark was the first to introduce Aprepitant (brand name Aprecap) a novel NK1 receptor antagonist in India.”

There are many chemotherapeutic drugs that have major side effects on patients. However, all side effects never come with a single drug. Each drug has its specific side effects. “For chemotherapy and other cancer drugs, there’s often a small window between active and toxic. Secondly each chemotherapic drug has differed in their adverse effects (hematological toxicity, nausea, vomiting, hair loss and certain organ damage). For example hydroxyurea, methotrexate will cause cytopenia, vomiting but not hair loss, where as anthracyclines, taxanes will cause cytopenia as well as hair loss,” informs Bhat.

‘Targeting’ side effects

Considering the hazards of chemotherapy, methods for long-term treatment, with minimal side effects continue to be investigated. Targeted therapy is one such approach that has evolved in the second half of the 20th century. Most targeted cancer therapies are in preclinical testing (research with animals), but some are in clinical trials.

“The anti-cancer drugs of the future will be far more effective with minimal adverse effects. The first of such drugs, imatinib, has results in a 95 percent cure of chronic myeloid leukaemia with none of the adverse effects one expects with chemotherapy. The number of these drugs is growing astronomically,” cites Deo. Sharma says, “Our recent focus is targeted therapy to improve quality of life in cancer patients. Gefitinib, an EGFR (epidermal growth factor receptor) based targeted therapy has been recently launched by ONKOS (a division of Glenmark dedicated to oncology), which is effective against non-small cell lung carcinoma.”

Awareness is the key

Making the patient aware of the nature and likelihood of side effects will definitely improve adherence and patient satisfaction. It will also enhance a trusting relationship with the healthcare provider. Though the doctor is the prime source of the information for the patient, even the doctor needs to learn about medicines from pharma companies as they are the product providers.

So at the end of the day the pharma company can and should play an important role in educating patients and doctors about the drawbacks of its products,. Glenmark has already taken steps towards this. Sharma informs, “As a company, it is a continuous endeavour of Glenmark to create total awareness about any drug we market, amongst the doctors. Clinical studies in the Indian population, an active pharmacovigilance program help us identify rare adverse events at times. In all forms of our communications, along with the efficacy and benefits, we also highlight safety parameters like the adverse effect profile, precautions to be taken and contraindications to be followed.”

Glenmark’s interaction is not confined to doctors only, as ultimately patients are the consumers of their medicines. Considering the importance of patient education about the possible effects of medicines, Glenmark has taken some initiatives. Giving more details on these plans, Sharma says, “At the patient’s level we intend to have maximum participation from the patient in various patient education programs. We conduct patient meetings in coordination with the consulting doctor to create awareness about possible adverse effects and ways to ameliorate symptoms. We also distribute patient education material in regional languages to increase awareness levels amongst patients. Any adverse event reported by a patient or physician is registered into pharmacovigilance registers and we constantly update physicians and patients with the latest literature available.”

Hope is the best medicine

Chemotherapeutic drugs deliver more than you bargain for. Though chemotherapy and side effects have always gone hand in hand, this scenario is set to change soon. The human angle and desperate efforts from researchers to minimise chemotherapy-induced miseries on cancer patients have resulted in discoveries of treatments like targeted therapy. We must accept finite disappointment, but never lose infinite hope. Let hope modern discoveries like targeted therapy will succeed in side lining the side effects.

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Link: http://www.expresspharmaonline.com/20080131/research01.shtml