By David N. Leff

Aging is hazardous to your health. Advancing years bring enhanced likelihood of death from cancer.

Most known risk factors - for example, tobacco for lung cancer - can be avoided, sworn off or mitigated to some extent, but malignancies are unavoidable fellow travelers of old age.

Ironically, they spell payback time for the earliest period in a person's life - gestation. As the growing embryo forms its future organs, its fast-multiplying cells rely on two developmental molecules - telomeres and telomerase - to keep their prenatal chromosomes on track.

Under the microscope, a human chromosome resembles a floppy capital letter "H." Somewhat the way a shoelace keeps its ends from fraying, by capping them with metal or plastic tips, the four endpoints of that H avoid fraying by piling on caps consisting of layer after layer of DNA repeats called telomeres.

While that developing embryo is building its future body, it adds to those protective DNA deposits by means of the enzyme telomerase. Once born, the newborn infant exchanges those deposits for withdrawals. Telomerase retires from the growth scene, and the telomeres cash in one DNA layer each time a cell divides. But sometimes, as time goes by, some event prods the dormant telomerase enzyme back to its original activity. It resumes adding telomere layers so that the cell starts dividing and multiplying as if it were back in second embryonic childhood. But this time the new growth spells cancer.

Why does this ticking time bomb explode later in life, as a rule, rather than earlier? Cancer geneticist and telomerase scientist Ronald DePinho explained: "As a function of continual age and cell turnover, what happens is that telomeres get shorter and shorter, because there are insufficient levels of telomerase to maintain them. As they shorten, they become dysfunctional, and chromosomes start wildly fusing with other chromosomes. That sets the stage for situations where as chromosomes get pulled apart to opposite daughter cells, those randomly merged chromosomes can break and generate free ends. These then might recombine inappropriately with other chromosomes, and generate the tremendous explosion of genetic chaos that then ensues. It's as if someone tossed a hand grenade into the cell's nucleus at some point during the development of that wannabe cancer cell.

"Most cells cannot tolerate that and will die," DePinho continued. "But rare cells will have reshuffled their genetic deck in such a way that they now have a pro-cancer genotype. So we speculated that perhaps telomeres may be very important for epithelial-cell cancers because as these continually turn over and renew themselves in life - as those cells walk the telomere plank into this dysfunctional state - perhaps that might generate a phase of chromosome instability, which then fuels the cancer process."

Lifetime Cell Turnover Fosters Cancer Proneness

DePinho is American Cancer Society Research Professor at the Dana-Farber Cancer Institute of Harvard Medical School in Boston. He is senior author of a paper in today's Nature, dated August 10, 2000, titled: "Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice."

"Humans, as they age," DePinho told BioWorld Today, "predominantly develop epithelial-cell cancers. These are the neoplasms that arise from tissues that undergo continual cell turnover - the lining of the intestinal system, the breast, the skin, the prostate, etc. All are tissues that undergo constant renewal throughout life.

"One of the basic differences between mouse and man," he pointed out, "is that mice typically develop soft-tissue lymphomas and sarcomas rather than solid epithelial carcinomas. What we did," he recounted, "was to engineer mice that experience age-dependent telomere attrition. We knocked out telomerase, which is normally expressed in mice, and those animals then underwent shortening of telomeres to a critically short length - just like humans. So we essentially humanized this mouse model.

"What ensued," he went on, "was a dramatic shift in the tumor spectrum of those mice, away from sarcomas and lymphomas toward the type of cancers that we typically see in aged humans. And what was rather interesting is that the cytogenetics of those particular epithelial tumors - breast, colon, skin - that came up in the mice were very complex and unstable. They had chromosomal rearrangements similar to the kinds that you see in the human counterpart.

"Now we must ask," DePinho continued, "whether what we've learned in the mouse is relevant to the human condition. First of all, we know that as tumors develop - a colon cancer for example - what we see first in an early precancerous polyp formation, which is the benign phase, is an explosion in chromosomal instability. And that is reminiscent of the kind of instability that we see in these engineered mice. It's only in the late polyp stage, as a transition from adenoma to carcinoma, that telomerase begins to be expressed.

"That activation of telomerase then quells the genomic instability, allowing for the additional subtle mutational gene events to occur to allow that tumor to mature, so that it invades, spreads and eventually kills its aging host.

"I think," DePinho summed up, "that the lack of telomerase, and continual cell renewal, put cells at risk for the development of cancers as a result of the associated genetic instability. That then sets in motion a series of events leading to progression, one of which is ultimately the activation of telomerase."

To Stop Tumor, Scotch Telomerase

"What this tells us," he pointed out, "is that maintenance of telomeres may be very important in preventing cancer. That could lead to the view that one road to take is to assess whether or not blunting telomere attrition may be beneficial as a preventive strategy against the development of tumors in these cancer-prone epithelial systems. Because there's a very tight association between increased cancer incidence and hyperproliferation in various cell types."

DePinho said, "For any cancer target that's identified, if you know a gene that is gained or lost in that tumor, that puts you on the path to being able to develop drugs that could potentially impact on the function of that gene. But," he concluded, "it also provides us with a mouse model that might give us more genes to go after."

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