May 29, 2003 A new study by Penn State College of Medicine researchers reveals for the first time one of the mechanisms by which malignant melanoma, the most deadly form of skin cancer, grows and spreads.
"Although the incidence of melanoma has been on the rise for years, few advances have been made in its treatment," said Gavin Robertson, Ph.D., assistant professor pharmacology, pathology, and dermatology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "These discoveries may lead to another crucial weapon in the rather small arsenal of treatments available for this dangerous disease and offer the first hope for a new melanoma treatment target in decades."
Robertson's study proves a role for an important gene called PTEN and suggests that PTEN dysfunction may be responsible in 30 percent to 60 percent of melanomas. The study entitled, "Loss of PTEN Promotes Tumor Development in Malignant Melanoma," appeared in the June 1 issue of Cancer Research. The research was supported by The Foreman Foundation for Melanoma Research.
The process leading to the formation of melanoma begins when a cell growing in the top-most layer of the skin is damaged, such as through severe sunburn. The damaged cells act as a melanoma trigger and, at first, the body's natural defense system is often able to fight them. But as they multiply, the melanoma cells develop new strategies to evade the body's immune system. The changes that occur in these cells are difficult to pinpoint and therefore, little is known about how and where they occur.
This study reveals PTEN as a target gene that is altered, enabling melanoma cells to form tumors. In non-cancerous cells, PTEN normally starts a chain reaction ensuring that malfunctioning and damaged cells are killed. In contrast, abnormal cancerous cells gain the ability to switch off PTEN, allowing the dysfunctional cells to survive and thrive. Accumulation of multiple changes like this in melanoma cells results in the development of a faster growing and more aggressive tumor.
Robertson used a leading-edge technique called chromosome transfer technology to transfer an entire chromosome 10 - about 5 percent of the genome - from healthy cells into the abnormal melanoma cells. The introduction of chromosome 10, which contains the PTEN gene, temporarily switched off the tumor cell growth in mice and allowed apoptosis, or cell death normally occurring in non-cancerous cells, to resume. Apoptosis made the cells behave more like normal cells, thereby clearing away the dysfunctional and damaged cells.
"When these normal genes are introduced into melanoma cells, they can no longer multiply," Robertson said. "It's essentially a red light telling the cells you can't form tumors."
Although this temporarily slows the growth, the melanoma cells eventually start to grow again, illustrating that tumor cells can learn to evade the "red-light genes" just as they become resistant to the treatment drugs that fight cancer.
"Cancer cells are tricky. The tumor cells find a way to get around the gene or treatment and begin to grow again," Robertson said. "That's what makes these cancers so deadly especially when they metastasize and move around the body; they become resistant to the therapies."
These results suggest that introducing PTEN into melanoma cells using a harmless virus carrying the PTEN gene could be a useful therapeutic approach for killing melanoma cells.
"As we add to the treatment possibilities, we give patients more chances to beat the cancer," Robertson said.
Robertson's most critical message: prevention.
Of the three forms of skin cancer, melanoma is the most likely to result in death. In 90 percent of cases, severe sunburns trigger melanoma. Each year the number of cases of melanoma increases by 4 percent, making it one of the cancers with the fastest increasing incidence in the U.S. In 2003, one in 65 people have a lifetime risk of getting the disease; it is projected that by 2010, one in 50 Americans will be afflicted by melanoma.
"Detected early, melanoma has a 100 percent cure rate," Robertson said. "If you've ever had sunburns, make sure you monitor moles and see a dermatologist once a year, and be sure to put sunblock on your children. Most, about 80 percent, of the sun damage accrued during a person's life occurs in the first 18 years of life."
Co-authors on the study were: Jill M. Stahl, Mitchell Cheung, Arati Sharma, Nishit R. Trivedi, Sumathi Shanmugam, Department of Pharmacology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center.
### The Foreman Foundation for Melanoma Research was formed to perpetuate the memory of John Bruno, Jr., a former member of the Penn State football team and retired professional football player who died of complications from melanoma in 1992. The mission of the Foreman Foundation is to raise funds for medical research that will lead to a cure for melanoma cancer, while heightening awareness as to the causes and symptoms of this disease. Since its founding, the Foreman Foundation has raised nearly half a million dollars for melanoma research.
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