Science / Medicine : Genes That Cause Cancer : Scientists Gain Insight Into Tumor-Suppressor Function

The study of oncogenes--genes that cause cancer--is one of the most promising approaches to understanding cancer, many scientists believe. Now, scientists are gaining insight into not only oncogenes but their “mirror images,” anti-oncogenes, which protect cells from cancer. Such studies, they say, may lead to the development of entirely new ways to treat cancer.

The first oncogene (from the Greek onkos, meaning mass or tumor) was isolated in the early 1970s from a virus that causes cancer in chickens. Researchers found that a single gene in the virus could cause the tumors. Biologists have subsequently found oncogenes in a variety of viruses.

The oncogenes are closely related to cellular genes that are responsible for the normal proliferation of cells, such as during infancy and adolescence. In fact, researchers believe most human cancers result when these normal genes are converted to oncogenes by chemicals, radiation or exposure to viruses.

Three years ago, researchers found a family of human genes whose function is almost the exact opposite of the oncogenes. They quickly dubbed these new genes anti-oncogenes or tumor-suppressor genes.

The discovery of the anti-oncogenes is “a tremendous breakthrough that, within the next decade, is going to have a tremendous impact on human cancer,” according to geneticist John Minna of the National Cancer Institute in Bethesda, Md. Researchers studying anti-oncogenes have been in a period of “feverish activity,” added molecular biologist Robert Weinberg of the Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research in Cambridge, and new discoveries are being made “unexpectedly rapidly.”

One potential use of anti-oncogenes for therapy has already been demonstrated. Molecular biologist Wen-Hwa Lee of UC San Diego and others have already shown that the addition of anti-oncogenes to tumor cells grown in the laboratory can convert the cells back into healthy, non-cancerous cells. While it may not be practical to add anti-oncogenes to tumors in humans, researchers hope that they can find simple chemicals that will mimic the activity of the anti-oncogenes.

One unexpected result of the research on oncogenes and anti-oncogenes, according to microbiologist Edward E. Harlow Jr. of the Cold Spring Harbor Laboratory in New York, is the recent discovery that at least four different types of viruses that cause cancer in animals and humans operate through a common mechanism.

Each of the viruses produces a protein that inactivates a recently discovered different cellular protein that acts as a brake on undesirable cell growth, Harlow has found. By canceling the activity of the restraining protein, the viral protein sets the stage for the unrestrained growth typical of cancer. That growth might then be triggered by a chemical carcinogen such as tobacco smoke, by radiation, or perhaps even by another virus.

As a result of that discovery, some scientists are concluding that the 100 or so different types of cancer actually represent a much smaller number of types that are clinically quite different, such as the rapidly proliferating cancer of the blood called leukemia and the much slower growing cancer of the colon, but that share a common mechanism at the molecular level. Researchers have feared that it would be necessary to develop a unique form of therapy for each of the 100 types, but it seems possible that cancers with similar mechanisms might ultimately be found susceptible to similar forms of therapy.

But the research has implications far beyond cancer research. Because the genes produce chemical signals that control the proliferation of cells, the research may shed light on such disparate processes as stimulating wound healing, initiating the production of more blood or immune cells in injured or ill patients, and perhaps eventually even in stimulating the growth and healing of spinal cords or the regeneration of missing organs or limbs.

According to molecular biologist Donald Coffey of the Johns Hopkins University School of Medicine in Baltimore: “Research on cancer may teach us more about biology than it does about cancer.”

Another major boost to the study of oncogenes--and one that was crucial to Harlow’s work-- was the discovery of the retinoblastoma (RB) gene in October, 1986, by ophthalmologist Thaddeus Dryja of the Massachusetts Eye and Ear Infirmary. The RB gene was like no other gene seen before. The gene protects the body against development of retinoblastoma, a rare eye tumor that affects about 500 children in the United States each year. Retinoblastoma occurs only when RB genes are inactivated.

Most people are born with two healthy RB genes, one from each parent, that protect them from retinoblastoma. Only rarely, about once in every 40,000 individuals, both RB genes in a single cell are damaged by chemicals, viruses or radiation, allowing a tumor to form.

Dryja and his colleagues, however, studied an inherited form of the disease. He found that children in such families inherit a normal RB gene from one parent and a defective gene from the other parent. In these children, only the healthy RB gene must be damaged before a tumor occurs. The process occurs so easily, they found, that many children from such families develop multiple tumors.

Dryja has developed a genetic test to identify children who are susceptible to retinoblastoma. These children can then be monitored closely to detect tumors in their earliest stages, when they are more vulnerable to therapy.

Were the RB gene linked only to retinoblastoma, it might be considered little more than a curiosity. But epidemiologists have found that children who survive retinoblastoma and grow to adulthood also have a high incidence of osteogenic sarcoma, breast cancer and small cell lung cancer. Researchers have found that many cells from such tumors are also missing the RB gene, suggesting that loss of the RB gene contributed to development of the tumors.

In 1987, molecular geneticist Eric Stanbridge of UC Irvine isolated chromosome 13 from healthy cells and inserted it into cultured tumor cells from an osteogenic sarcoma, a form of bone cancer, and found that the chromosome caused the cells to revert to normal. That feat has subsequently been duplicated with other chromosomes and other cancers. Last December, Lee demonstrated that the retinoblastoma gene, which is found on chromosome 13, can cure the osteogenic sarcoma cells by itself.

Lee has been studying the protein that is produced by the RB gene and has found that it binds to deoxyribonucleic acid (DNA), the cell’s genetic blueprint. He and others believe that this RB protein binds to certain sites in a cell’s DNA and thereby prevents the activity of genes that promote cellular growth.

Researchers now know that a whole family of genes similar to the RB gene exist throughout the body to regulate growth. Studies have shown, for example, that many colon cancers are missing a segment of chromosome 5 that presumably carries an analog of the RB gene, while other tumors have been found to lack sections of chromosome 11.

Harlow’s group, working with MIT’s Weinberg, found that an oncogene-related protein called E1A binds to the RB protein, “the first example where the product of an oncogene binds to the product of an anti-oncogene,” Harlow said. The binding of the two proteins prevents the RB gene from functioning--in effect, releasing the brake on the cell. The cell is then free to respond to other growth stimuli, which leads to tumor formation.

Speaking at a recent American Cancer Society symposium in Irvine, Harlow said oncogenes in other cancer-causing viruses also bind to the RB protein. The SV40 virus, which causes tumors in monkeys, makes a protein that binds to the RB protein. So too do all polyoma viruses, which cause cancer in animals and cultured cells.

Perhaps most significant, the papilloma virus has a protein called E7 that binds to the RB protein. The papilloma virus, Harlow said, “is associated with 90% of cervical carcinomas in humans.” It is not yet clear why the other viruses are unable to cause cancer in humans. “Undoubtedly, the body has worked out ways to defend against these viruses,” Weinberg said.

That conclusion may itself be important. If researchers can discover how the body fights off some cancer-causing viruses, they may be able to learn how to fight off others.