Scientists Shed Light on Fatal Skin Tumors

August 19, 1999

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By William J. Cromie
Gazette Staff

Lynda Chin and her colleagues have learned how to stop the growth of human skin-cancer tumors growing in mice. Photo by Kris Snibbe

Researchers have discovered how to choke off the survival of melanoma tumors, the deadliest form of skin cancer. The experiments were done in mice, but the animals carried a human gene, mutations of which cause a malignancy that is the top cancer killer of white women between 25 and 30 years old.

The gene, called ras, produces a protein vital for the growth of organs and tissues, but mutations of it can cause an out-of-control proliferation of cells that typifies cancer. Investigators at Harvard Medical School developed a system whereby this mutated gene can be switched on and off. By doing so, they found that mutated ras plays a role in both the origin and maintenance of melanoma tumors.

Because ras is found in many different human tumors, "this mouse model gives us the opportunity not only to better understand and treat melanoma, but to learn about the genesis and survival of other kinds of solid tumors," notes Lynda Chin, an assistant professor of dermatology who works at the Harvard-affiliated Dana-Farber Cancer Institute in Boston.

"It takes more than one mutation to turn a healthy cell cancerous, but our experiments show that we do not have to identify and treat every genetic mistake," Chin explains. "Rather, we can successfully treat tumors by targeting key genes like ras."

Identification of these critical genes should provide specific objectives for anti-cancer treatments. Such therapies would include replacing defective genes, or designing drugs that inhibit their activity. Various drug companies are already working on anti-ras drugs.

Ras mutations appear in breast, prostate, lung, and colorectal cancers — the biggest killers of men and women in the United States. Therefore, lessons learned from melanoma mice may well increase the understanding of these cancers and help produce new types of treatments for them.

Tumors Commit Suicide
Chin and colleagues from Harvard, the Albert Einstein College of Medicine and Memorial Sloan-Kettering Cancer Center in New York City, and Regeneron Pharmaceuticals made mice with a mutated human ras gene coupled with a way to turn the gene on and off. When the rodents drank water laced with an antibiotic called doxycycline, the gene was activated, and 25 percent of the mice developed melanoma tumors.

Once tumors formed, researchers withdrew the spiked water. That turned off ras activity, and within two to three weeks the tumors dramatically melted away.

Examinations by microscope showed that the tumor cells died by a process (apoptosis) equivalent to committing suicide. Also, blood vessels that formerly brought life-sustaining nutrients and oxygen to the tumors had collapsed.

"This outcome provided the first evidence that a genetic mutation is crucial for the maintenance, as well as the initiation, of a cancer tumor," Chin points out. "Moreover, we found that turning off the mutated ras destroys blood vessels that feed the tumor. Further study will undoubtedly uncover other processes important in maintaining tumor survival."

Fatal Sunshine
Melanoma is increasing at an alarming rate in the United States and several other nations, including Australia. Although it accounts for only 5 percent of skin cancers in the United States, it causes 75 percent of skin-cancer deaths — about 7,200 a year. Health experts expect as many as 37,000 new cases this year.

About 10 percent of these cases arise from inherited genes that predispose people to the disease. In others, ultraviolet light and, perhaps, other environmental factors cause mutations that lead to melanoma. "It’s all genetic at some level," Chin comments.

At present, the best treatment, particularly for fair-skinned people, is to limit exposure to the sun and undergo regular skin exams. If telltale irregular moles are detected early, when the cancer is still limited to the upper layer of skin, surgery offers a high cure rate. But once the tumor grows deeper into the skin and cancer cells spread beyond the surgeon’s blade, no effective treatment exists.

The hope is that further experiments with animals, carried out by Chin’s team and other groups, will lead to such treatments.

"The most exciting part of this work is that it not only addresses melanoma specifically, but it sheds light on how tumor cells in general instruct a host body to construct an environment that permits and sustains tumor growth," Chin says. "The cells somehow figure out how to evade the body’s natural defenses and to co-opt resources for growth and for building a blood supply. A similar process must operate in other types of solid tumors that form in breasts, prostate glands, lungs, and colons."

Chin and her colleague Ron DePinho, a professor of genetics at Harvard Medical School, believe that new technologies now coming into use will allow researchers to identify which genes are turned on and which stay off as tumors establish themselves in a human body. "Once we determine the genes involved, and the signals they send to each other," Chin concludes, "we can design specific therapies to make a host’s environment uninhabitable by the tumor cells."

The work of Chin, DePinho, and their colleagues was described more fully in the July 29 issue of the journal Nature.