Cancers follow shrinkage of chromosomes' tips. (Split Ends).

Molecular caps that normally protect the ends of chromosomes shrink in many cells that later turn cancerous, according to a new study in people.

Just as shoelaces that lose their plastic tips unravel, so may chromosomes with broken tips, or telomeres, be more prone to mutations that cause cells to become cancerous, says Alan K. Meeker of Johns Hopkins Medical Institutions in Baltimore. His new findings, which are based on studies in a variety of human tissues, support that popular hypothesis.

Past studies had confirmed that telomeres are abnormally short in human cancer cells. The phenomenon could be a product of cancer cells' rapid replication, because telomeres commonly shrink slightly with each round of cell division. However, studies in mice have suggested that short telomeres lead to cancer, and not vice versa. Six years ago, scientists found that mice that lack an enzyme involved in maintaining telomere length are predisposed to develop certain cancers (SN: 10/11/97, p. 228).

Meeker and his colleagues reported last year that, in people, telomere shortening usually precedes cancer of the prostate and pancreas and may therefore contribute to the development of the disease in those tissues.

To see whether telomere shortening also presaged other human cancers, Meeker and his team examined dozens of tissue samples from precancerous lesions that surgeons had removed from people. Samples came from the bladder, breast, colon, esophagus, mouth, and cervix. All of these are organs that, like the prostate and pancreas, are formed from so-called epithelial tissue.

Using a technique that causes telomere DNA to fluoresce under a microscope, the researchers scrutinized tissue samples in which some cells had a precancerous appearance.

Most of these samples contained chromosomes with abnormally short telomeres, Meeker reported in Washington, D.C., at the annual meeting of the American Association for Cancer Research last week. Eighteen of 23 breast lesions examined and 45 of 46 lesions from other parts of the body had some cells with telomeres so short that they weren't visible in microscope images. Those images nevertheless showed normal telomeres in neighboring, apparently healthy cells, Meeker says.

Telomeres in lesions were as short as those commonly seen in full-blown tumors. This similarity indicates that telomere shortening precedes the development of cancer rather than being a product of it, says Angelo DeMarzo, who worked with Meeker on the new research.

The findings appear to confirm that the erosion of telomeres helps drive the genetic instability required for cells to become malignant cancers, says geneticist Ronald A. DePinho of Harvard Medical School in Boston.

The earliest clinical applications of the findings are likely to be diagnostic, DePinho says. Screening for telomere shrinkage among people at risk for epithelial-tissue cancers might identify tissues in "extremely early stages of malignancy," he says.

In the future, preventive treatments might maintain telomere length and thus mitigate chromosomal changes in people at high risk of cancer, says DeMarzo. Telomere length could also be used to measure the effectiveness of certain other treatments designed to prevent cancer, he says.