A gene that enables the skin's pigmented cells to survive harsh sunlight may have a darker side as well, making the deadly skin cancer, malignant melanoma, highly resistant to treatment.
This is the discovery of scientists at Dana-Farber Cancer Institute (DFCI).
Sunbathers enjoying the summer rays can thank the body's "natural sunscreen" -- a layer of pigmented cells -- for preventing much damage to the body. In turn, those dark-colored cells themselves might be destroyed by solar radiation if they didn't contain a protective mechanism that allows them to survive.
The findings, reported in today's issue of the journal Cell, "may explain why tumors that arise from melanocytes (pigment-producing skin cells) are particularly resistant to chemotherapy and radiation," says David Fisher, MD, PhD, a Dana-Farber researcher. "Melanoma is one of the most difficult tumors" to try to combat with cancer therapies.
An estimated 53,600 Americans will be diagnosed with melanoma this year and 4,700 Americans will die from the disease, according to the American Cancer Society. Melanoma accounts for about only 4 percent of skin cancer cases, but it causes about 79 percent of skin cancer deaths.
Fisher is the senior author of the paper, which is featured on the cover of Cell, that describes a series of experiments that were conducted during the past several years. Gael McGill, a graduate student, and Martin Horstman, a postdoctoral fellow in the Fisher lab, are first authors.
The report implicates a gene, known as MITF, in enabling both normal and malignant cells to escape apoptosis, a natural process that triggers suicide in a cell that has reached the end of its useful life cycle.
Apoptosis kicks in when a cell's DNA is damaged, assigning it to death rather than risk chaotic, dangerous reproduction by the errant cell.
Many cancer drugs work by inducing cancer cells to undergo apoptosis instead of continuing to divide unchecked.
The sunscreen cells, the melanocytes, are continuously bombarded by ultraviolet solar radiation as they generate pigment which protects underlying skin cells.
Ordinarily, the melanocytes would become damaged from the radiation and apoptosis might be initiated -- unless there were some countervailing force. And there is: During human evolution, melanocytes appear to have acquired at least one such mechanism that neutralizes apoptosis and enables the cells to survive.
The main players in this apoptosis-blocking game are MITF and another gene with which it interacts, BCL2.
The MITF gene, dubbed by scientists as "the master melanocyte regulator," is found in melanocytes and is critical for their proper development and their long-term survival.
In addition, MITF is thought to play a key role in production of pigment by these cells. BCL2 is a cell-death suppressor, many of whose actions were discovered by Dana-Farber researcher Stanley J. Korsmeyer, MD.
When either the MITF or BCL2 gene is mutated or missing, the whiskers and fur of mice turn from black to gray or white because melanocytes have died. A mutant MITF gene is involved in a human genetic disorder that causes, among other abnormalities, locks of white hair from birth.
The investigators used microarrays, or "DNA chips," to determine what genes are turned on when the MITF gene is active, i.e., what genes are "targets" of MITF within normal melanocytes. The microarray experiments showed that the protein produced by MITF links up with the BCL2 gene both in normal melanocytes and in melanoma cells, increasing the amount of BCL2 protein being made, and activating cell survival.
McGill and others in the Fisher lab also inhibited the activity of MITF in melanocytes and melanoma cells by infecting them with genetically engineered viruses. When the viruses blocked the action of MITF, the cells died.
By the same token, the researchers could artificially rev up the activity of BCL2 in MITF-inhibited melanoma cells, thereby enabling them to survive. In this instance the BCL2 genes' pro-survival action overcame the apoptosis signals.
MITF therefore appears to regulate both pigmentation and survival through its actions on BCL2, explains Fisher.
"While such a connection between pigmentation and survival is probably beneficial for normal pigment cell function, the flip side is that it may confer super survival properties and impede successful therapy in melanoma," says Fisher, who is also an associate professor of pediatrics at Harvard Medical School.
He and McGill noted that while experimental drugs that block BCL2 are being tested as potential cancer treatments, there is no current clinical application of the new findings. Blocking MITF is a theoretical strategy for treating melanoma but that is only speculative at this stage, they said.
The paper's other authors include investigators from the laboratories of Korsmeyer and Todd Golub, MD, of Dana-Farber and the Whitehead/MIT Center for Genome Research and Ian Jackson from the MRC Human Genetics Unit, Western General Hospital in Edinburgh, Scotland.
The research was funded by grants from the National Institutes of Health, Bristol-Meyers Squibb, Millennium Pharmaceuticals and Affymetrix.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. - By Bill Schaller
[Contact: Bill Schaller]