Telomerase and Tumor Suppressor Link Up

Two studies published in the May issue of Cell shed more light on the connection between telomerase, tumor suppressors, and cancer. Researchers at Dana-Farber Cancer Institute report that the same system that protects against cancer can, in some circumstances, actually promote malignancy. Using a cancer-prone mouse species and several knock-out strains, these studies reveal the effects of the combined losses of telomerase and tumor suppressors on the development of cancer.

The research was performed in the laboratory of Ronald DePinho of Dana-Farber and professor of medicine (genetics) at Harvard Medical School.

"The studies confirm much of the conventional thinking about the nature of cells' natural defenses against cancer," says co-lead author Lynda Chin of Dana-Farber and assistant professor of dermatology at Harvard Medical School. "But they also show that some cancer cells have the ability to evade these defenses in ways that make them extraordinarily difficult to target with single therapies."

The studies deal with a key point in the life of a cell known as "crisis," the point at which the signal for a cell to stop dividing takes hold. In normal cells, this occurs around 50 to 60 cell divisions, the so-called "Hayflick limit." Sometimes, a genetic mutation enables cells to bypass the Hayflick limit and continue to divide. With each division, the telomeres get shorter and shorter until they are severely eroded. With the loss of telomeres and their chromosome-protecting function, the chromosomes start fusing with one another, breaking and rearranging, resulting in a scrambling of the cells' genetic programming

At this point, cells somehow sense that something has gone awry and activate apoptois, or cell death, believed to ensure that genetic scrambling is not passed on. It is here that cells are considered to be in crisis.

"Cells are programmed to sacrifice themselves so that genetic abnormalities are not perpetuated," says Chin.

To study this process, the group bred successive generations of mice that lacked the ability to rebuild their telomeres and lacked one of two key tumor suppressor genes, p53 or INK4a. p53 is the most common tumor suppressor gene to be found in mutated form in human cancers. The INK4a gene is second only to p53 in its involvement in human cancers. Losing either one of these genes is thought to predispose an organism to develop cancers.

In the first study, entitled "Tumorigenesis in the INK4 Cancer Prone Mouse," the researchers looked at tumor formation in mice lacking telomerase and the tumor suppressor, INK4 and found that with each successive generation of mice, the percentage of mice with tumors decreased, as researchers had expected. In the first generation of "crisis" mice, 64% of the animals developed cancer; in the third generation, 50% did; and in the fifth generation, 31% did. At the same time, the survival rate of the mice rose with each generation—from 12% in the first generation to 54% in the fifth.

"This represents the first proof that telomere-shortening during crisis inhibits the growth and creation of tumors," Chin says. "Without intact telomeres, cells have a harder time dividing and proliferating."

But if crisis is indeed a tumor suppressor, it is an imperfect one, the study found. While successive generations of mice had fewer tumors, some tumors did develop. Within those tumors, researchers found a high frequency of chromosomal fusions. The authors speculate that these fusions help preserve the integrity of the genetic materials within the chromosome.

In the second study, "p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis," the researchers turned their attention to the common tumor suppressor p53. It had been theorized that the erosion of telomeres during crisis represented a trigger to apoptosis; telomere loss would activate p53 and set cell suicide in motion. The researchers found that this is indeed the case.

"This demonstrated for the first time that p53 responds to the erosion of telomeres in the same way that it responds to other kinds of DNA damage: by initiating the process of cell death," says co-author Steven Artandi.

However, the p53-mediated attenuation of tumor formation only occurred during the earliest stages of genetic crisis. When the researchers looked at the most recent generation of p53-deficient mice—eight generations removed from the first set of "crisis" mice—they identified a stage of cancer development that they call "genetic catastrophe." At this stage, cancer-prone cells are so genetically unstable as a result of the crumbling of telomeres that the cells have only two courses open to them—death or further progress toward cancer. Cells that are unable to adapt to the disruption of their genetic material die. Cells that can adapt—by rebuilding their telomeres, by fusing their chromosomes in ways that enable them to still function, or by other unknown, responses—continue to divide relentlessly, and are one step closer to becoming fully malignant.

This study establishes a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, and shows that therapies that seek to arrest cancer by preventing cells from rebuilding their telomeres may be less effective in cells that lack functioning p53. The authors conclude that telomerase-targeting therapies should be different for p53 competent versus plus versus p53 deficient tumors.

For more information: Ronald DePinho, Professor of Medicine (Genetics), Dana Farber Cancer Institute, 44 Binney Street, Mayer 6, Boston, MA 02115. Tel: 617-632-4090.