Newfound gene linked to cancer growth Defect in protein may help tumors resist

January 04, 1996|By NEW YORK TIMES NEWS SERVICE

Scientists at Stanford University and elsewhere have gained an important insight into the basic biology that underlies the evolution of cancerous tumors. Their finding explains why many solid tumors are resistant to chemotherapy and radiation from they moment they are found, and why some cancerous cells can survive even in the center of tumors, where there is very little oxygen.

This insight, if confirmed, should provide a better understanding of how tumors develop, as well as new therapies for interfering with the process.

One expert not associated with the new work, Dr. Bert Vogelstein, a cancer researcher at the Johns Hopkins University School of Medicine, said it could be a milestone in efforts to understand the origins of cancer.

The new study, by Dr. Amato J. Giaccia of Stanford University and his colleagues, relates the evolution of solid tumors to a recently discovered gene that is of central importance to the birth and death of cells. The gene produces a protein called p53 that serves as a natural emergency brake to arrest any runaway growth by cells that may have acquired cancerous tendencies.

In one of its roles, p53 stops the proliferation of a potentially cancerous cell by binding to a pivotal site on the cell's DNA and blocking the process of cell division.

But p53 also has another emergency property: It can activate a mechanism that causes an aberrant cell to disintegrate. Thus the center of solid tumors is often full of dead or dying cells that have been launched into self-destruction by their p53 genes.

Because of these properties, the p53 gene is known as a tumor-suppressor gene. But what stimulates the cell to produce p53?

Last year, evidence came to light suggesting that lack of oxygen might be a natural trigger for p53 production. Following up on this hint, Dr. Giaccia and his colleagues made two significant findings.

One is that lack of oxygen does indeed bring on production of p53 and cell death in many cancerous cells. The second is that some cancerous cells develop mutations in their p53 gene, and the defective p53 protein is no longer able to constrain their growth. These mutated cells, in low-oxygen conditions, have an enormous competitive advantage and soon dominate in the central regions of solid tumors.

The finding would explain why such cells are resistant to radiation and chemotherapy, which kill cells by damaging their DNA and causing p53 production: In the mutated cells, p53 is no longer effective.

The finding also sheds light on the early stages of tumor development, suggesting that tumors start off very slowly, with a balance between the forming of new cells and the forced suicide of existing cells. Only when the p53 gene mutates does the tumor spin out of control.

The new findings were made in mice, whose cells are believed to work much like human cells in this respect. Dr. Giaccia said in a telephone interview that he had preliminary evidence that the same process had occurred in tumors removed from patients.

Cancer experts said Dr. Giaccia's paper, being published today in the journal Nature, shed new light on the development of cancer.

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