The image above, generated by spectral karyotyping, show individual chromosomes by unique colors. The chromosomes at left are from mice with intact telomeres; those at right are from mice with dysfunctional telomeres. The arrows point to chromosomes with multiple colors, indicating that chromosomes have been broken and rearranged. The process of chromosome breakage and translocation creates massive changes in cells' genetic programming, potentially leading to cancers of the skin, colon, breast, and other sites.
A common thread running through both cancer and aging is damage to DNA, the molecule providing the blueprint for cellular proteins. As cells lose their ability to make critical proteins, they start to malfunction, and many eventually die. But no one, as yet, has defined the underlying process of damage that leads to either cancer or aging. It could be perpetrated by excess sugar, by highly reactive molecules called "oxygen radicals" made as a byproduct of cell metabolism, or other causes. Scientists once suspected that the absence or disruption of one or two genes might be sufficient to make a cell cancerous.
Ronald DePinho, M.D.Today, scientists widely recognize that to become cancerous, cells usually must undergo widespread changes in their genetic make-up. The entire cancer cell is often unstable, with different genes interacting in abnormal ways. Many genes, perhaps hundreds or thousands, may be missing or malfunctioning in the cells of full-blown tumors.
Fortunately, the body has many defenses against genetic instability and cancer. Cells make enzymes and proteins that protect DNA at vulnerable times. A gene called p53 can automatically shut down cell growth if there's a chance of an abnormality occurring that might lead to cancer. Another protective mechanism is normal cell death, or "apoptosis," a complicated mechanism by which cells commit suicide for the good of the entire organism.
"Apoptosis is sometimes a way for damaged cells to do the honorable thing and 'off themselves' so they don't become a threat to the rest of the host," says Korsmeyer. "Aging is a very complicated issue, and if you had a disorder in apoptosis, it would almost certainly shorten lifespan."
Even before they die, most human cells enter a condition called "senescence" — a literal translation might be "oldness" — after they have undergone 40 to 80 cell divisions. Theoretically, senescent cells seem unlikely to play a role in cancer, the hallmark of which is uncontrolled cell growth.
"Apoptosis is sometimes a way for damaged cells to do the honorable thing and 'off themselves' so they don't become a threat to the rest of the host."
— Stanley Korsmeyer, M.D.M.D.
If you wanted to find a way to prevent cancer from arising in older cells, senescence would appear to be a good approach. It's generally believed, in fact, that one of the purposes of this senescent period is to prevent cells from replicating at the time when they are most likely to be flawed and give rise to cancer.
How do these innocuous-looking, older cells become so dangerous? Researchers at DFCI believe they have discovered how DNA may become scrambled and unstable in older cells, in large part through recent investigations into an important part of the cell called the telomere.
Inside the cell's nucleus, DNA loops around within the chromosomes. Telomeres, which protect the chromosome's end like the cap at the end of a shoelace, enable genetic material to safely and efficiently split in half when cells divide. But telomeres shorten as cells age, to the point where the cell can no longer divide and becomes senescent.
In recent experiments with mice, DFCI oncologists Ronald DePinho, M.D., and his associates Steven Artandi, M.D., Ph.D., Sandy Chang, M.D., Ph.D., and Lynda Chin, M.D., showed how cells with short telomeres might be extremely vulnerable to the type of dramatic cellular changes that lead to cancer. Mice normally develop the same types of tumors seen in younger people — those of muscle, bone, and kidney.
But when DePinho and Artandi bred mice with short telomeres, and without the p53 gene that normally shuts off cell growth in risky situations, they found something unexpected. The mouse tumors began to look like the genetically complex epithelial tumors normally seen in older people — cancers of the skin, colon, liver, and breast.
"Telomeres are not the clock, but they probably enable cells to respond to stresses often associated with aging."
— Ronald DePinho, M.D.
Something about the shorter telomeres changed the quality of the mice's cancers. DePinho, who with James Horner directs DFCI's Transgenesis and Gene Targeting, believes shortened telomeres permit chromosomes and DNA to break and recombine in unpredictable ways, sometimes leading to the growth of epithelial tumors.
"The epithelial cancers we see in adults are very difficult to generate; for these cancer types to emerge, more than just a few 'hits' to the cell's DNA are required," says DePinho. "But the erosion of telomeres and the onset of instability are very efficient at making rapid, wholesale changes in DNA. This telomere- based chromosomal instability appears to be a common mechanism through which epithelial cells generate the high level of instability needed to have a chance of generating a tumor. It's a conceptual leap, but it may help explain this unusual phenomenon."
