The Cancer - Chromosome Connection

by National Cancer Institute

(Page 8 of 9)

1986 -1992

TECHNIQUES FOR STAINING DNA grew steadily more sophisticated, molecular biology and molecular genetics advanced, and scientists made great leaps in establishing the link between chromosomes, the genes they carry, and cancer. Typically, cancer occurs when a series of damaged genes accumulate in a cell that eventually becomes cancerous.

Tumor Suppressor Genes: Natural Controls

In children with the hereditary form of the eye cancer known as retinoblastoma, Webster Cavenee showed that both copies of chromosome 13 lacked crucial DNA-supporting the hypothesis that some cancers are the result of a "two-hit" process. In 1986 researchers led by Thaddeus Dryja, Stephen Friend and Robert Weinberg isolated and cloned the missing gene-the first human tumor suppressor gene. While oncogenes promote cell growth, suppressor genes restrain it. Cancer can develop when the natural suppressors are damaged or lost.

Oncogenes: Uncontrolled Growth

An intensive search for the products of oncogenes revealed a fascinating relationship between cancer and the normal growth process. Experiments by Tony Hunter and others showed that many oncogenes encode molecules that are intimately linked to normal cell growth and behavior. These include growth factors and growth factor receptors, as well as enzymes that transmit signals across the cell and spur DNA into action, leading to cell division.

Growth Factors and Their Receptors

The discovery of nerve growth factor and epidermal growth factor by Stanley Cohen and Rita Levi-Montalcini, recognized with a Nobel Prize in Medicine in 1986, led to the revelation that growth factors play a role in the development of cancer. Several of these hormone-like secretions, which boost cell growth, and the receptors that welcome them into the cell are being exploited in caner prognosis and treatment.

Proofreading for Cancer

Common cancers often result from an accumulation of changes involving both tumor suppressor genes and oncogenes. In colon cancer, alterations in one or two genes can lead to benign polyps in the bowel; additional defects turn the polyps cancerous; and further changes prompt metastases. The mid-1990s experiments of Bert Vogelstein, Albert de la Chappelle, Richard Kolodner and others identified a new category of gene. "Proofreader" genes ordinarily repair defective DNA. If they mutate, havoc erupts-often in the form of cancer.

Proto-Oncogenes: Life or Death

Proto-oncogenes are normal genes which can change into their deadly alter-egos, oncogenes. The proto-oncogene bcl-2 (discovered in B-cell lymphomas) prevents cells from dying. The gene's intended role is to prolong the life of "memory" cells in the immune system. When activated inappropriately, bcl-2 allows quantities of white blood cells to accumulate and eventually mutate to produce the cancers known as lymphomas and leukemias.

Carcinogens: Telltale Triggers

Evidence linking specific environmental carcinogens to telltale DNA damage emerged in 1991. Radiation from the sun produces a characteristic change in the tumor suppressor genes in skin cells, while a different mutation in liver cancer can suggest exposure to either aflatoxin, a fungus poison, or to the hepatitis B virus. Chemicals in cigarette smoke switch on a gene that makes lung cells vulnerable to the chemicals' cancer-causing properties.

Exploiting Oncogenes

Researchers quickly learned to use the versatile oncogenes to advantage, as indicators of prognosis, markers of risk, or prime targets of therapy. In 1987 Dennis Slamon linked copies of one type of oncogene to a poor outcome in breast and ovarian cancer; by 1990 Mary Claire King had reported on a tumor suppressor gene associated with certain inherited breast cancers. The presence of oncogenes began to figure into decisions on type of treatment and, for some women, raised the question of prophylactic breast removal. In a variety of experimental studies, patients with breast, ovarian and lung cancer received monoclonal antibodies or drugs designed to disable oncogenes or oncogene products.

The Cancer Genome Anatomy Project

The Cancer Genome Anatomy Project is a computer database project that will assemble the first full index of genes involved in cancer. Cloned gene transcripts for normal, precancerous and malignant cells from lung, prostate, colon, breast or ovary will be available via Internet for all researchers.

The Human Genome Project

The efforts of scientists to pry loose the secrets of genes are intensifying as the 20th century draws to a close. The Human Genome Project, undertaken in the mid-1980s, is a multi-billion-dollar international collaboration to pinpoint the location and function of each of the estimated 50,000-100,000 genes that make up the inherited set of "instructions" for the functions and behavior of human beings. The U.S. research effort, which began in 1991, is jointly headed by the Department of Energy and the NIH's National Institute for Human Genome Research.

A New Era in Medicine: Gene Therapy

As knowledge of the human genome grew, researchers began to focus on the possibilities of gene therapy-replacing defective or missing genes with normal genes. In 1989 NIH researchers performed the first approved gene transfers, inserting foreign genes to track tumor-killing cells in cancer patients. This project proved the safety of gene therapy; by 1993 the NIH Recombinant Advisory Committee had approved more than 40 proposals for gene therapy targeting not only classic genetic diseases such as cystic fibrosis but also cancer and AIDS.

Genes As a Weapon

The first trial of gene therapy came in 1990, involving children with an inherited, life-threatening immunodeficiency disease. The children received a harmless virus, which carried copies of a normal gene into their T-cells. There, the normal gene replaced an abnormal gene that prevented production of a crucial enzyme. The experiment successfully restored immune defenses, and within months gene therapy trials extended to cancer.

Researchers removed special immune cells from patients with skin cancer, inserted a gene which boosted the immune cells' production of a natural killing factor, and grew the restructured cells in a laboratory. When reinjected, the immune cells fought the cancer with renewed vigor.

In a Trojan horse assault on brain cancer, Kenneth Culver and Michael Blaese put a gene that confers sensitivity to an antiviral drug into a harmless virus. Then they put the virus into mouse cells, and the mouse cells into a human brain tumor. In the human brain, the mouse cells release viruses, and the viruses invade dividing tumor cells, carrying with them the new gene. The new gene makes the human brain tumor cells susceptible to killing by an antiviral drug.

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