Study Points To Cell "Crisis" As Key Event In Development Of Cancer In Older Adults

The theory is that in tissues that undergo continual renewal, a process where cells die and are replaced throughout life, such as those in the breast, skin, prostate, and colon - a genetic mutation causes some cells to keep dividing even after their chromosomes have lost their protective protein ends called telomeres. The result is chromosomes that fuse together in abnormal ways, creating chaos with cells' genetic programming and setting them on the path toward cancer.

The new study, led by Ronald DePinho, M.D., and colleagues Steven Artandi, M.D., Ph.D., and Sandy Chang, M.D., Ph.D., of Dana-Farber, and published in the August 10 issue of Nature, involved the development of a new strain of mice whose ability to develop certain cancers resembles that of humans.

Normally, mice with flaws in their genetic "brakes" against cancer develop lymphomas and malignancies known as sarcomas in bones and connective tissue. In aging humans, however, tumors tend to arise in "epithelial" cells-cells that regularly die and are replaced--that line the interior of certain organs.

The DePinho team speculated that reason for this difference lay in the telomeres. In humans, telomeres shorten each time a cell divides until they become so short they can no longer protect the chromosomes from damage. At this point, known as the "Hayflick limit," the cells normally cease dividing. In some cells, however, a genetic error enables them to bypass the Hayflick limit and continue dividing even though their chromosomes are virtually shorn of telomeres. At this stage, known as "crisis," the cells' chromosomes begin breaking and fusing in abnormal places.

"When these complex chromosomal rearrangements occur, you get very rapid gains and losses of genetic information within cells," lead author Artandi says. "This process, known as "crisis," gives rise to pre-cancerous cells that begin to form a primary tumor, but cannot fully develop until telomere function is restored." At this point, full maturation of the cancer is achieved by reactivation of the enzyme telomerase, rebuilding and stabilizing the cells' telomeres -- and allowing continued tumor cell division and migration within the body.

"We have long known that cancer is associated with age," senior author, DePinho remarks. "We know it tends to occur in epithelial cells in older adults, and we know the chromosomal structure of these cancer cells is very complex: under a microscope, it looks as though someone threw a grenade into the nucleus where the chromosomes are located. We wanted to find an explanation for these phenomena."

The answer would come from studies with mice. In mouse cells, unlike human cells, the gene for rebuilding telomeres is always switched "on," so the telomeres don't shorten with each cell division. This has been thought to explain why mice tend to develop cancer in different tissues than aging humans do. DePinho and his colleagues developed a strain of mouse in which, like humans, the telomere-building gene is shut off. "Essentially, we engineered the mouse cells to experience 'crisis,' something they would normally be prevented from doing," DePinho says.

The results were striking. "We saw a dramatic shift in the types of tumors these animals developed," DePinho continues. "They much more closely resembled the tumor spectrum found in aged humans."

Not only that, but when the chromosomes in the mouse cancer cells were examined by Sandy Chang with a new technology called SKY (for Spectral Karyotyping), the patterns they formed were very much like those seen in cancerous epithelial cells in humans. Chang's efforts were greatly facilitated by the Arthur and Rochelle Belfer Cancer Genomics Center at Dana-Farber, directed by Lynda Chin, M.D., and Matthew Meyerson, M.D., Ph.D.

"Our conclusion is that crisis is a major event in the development of cancer cells in older people," DePinho remarks. "Crisis is what enables the cells to gain and lose the chromosomal material that leads cells to become cancerous."

The implication is that if crisis could be prevented -- by rebuilding the telomeres of cells before they incur the genetic instability associated with loss of telomeres -- scientists could prevent this crisis stage from occurring and, potentially, reduce the chances that the cells would become fully cancerous. Ongoing studies will explore that possibility. These studies were initiated by Lynda Chin and aided more recently by Scott Alson, Geoff Gottlieb, and Luan Lee.