Telomere shortening may cause significant alterations at the chromosomal level of tumors initiating chromosomal instability and causing progression to a fully malignant state. Telomeres are specialized structures located at the end of chromosomal arms that stabilize and protect chromosomes. In addition, they play a role in preventing cells from reproducing uncontrollably.
"Our study found that short telomeres may represent useful markers for assessing effectiveness in cancer chemoprevention studies," according to Alan Meeker, research fellow and lead investigator of the study which was conducted by researchers at the Brady Urological Institute and Department of Pathology, The Johns Hopkins University School of Medicine. "In addition, if telomere shortening does play a direct, causal role in the cancer process, then it represents an important prevention target in its own right."
In order to test the hypothesis that telomere shortening is an early contributor to human prostate cancer, the researchers developed and validated a new test that allows direct assessment of telomere length in clinical specimens. This study probed telomere lengths in high-grade prostatic intraepithelial neoplasia (HGPIN), the pre-invasive precursor to prostate cancer. Results showed that the telomere lengths of epithelial cells (relating to cellular tissue) within HGPIN lesions were strikingly shorter than those of adjacent normal-appearing epithelial cells in 93 percent of lesions examined.
Human tissues from prostate cancer patients, ranging from 47 to 67 years of age, were tested through microscopic examination of prostate tissue sections hybridized with a telomere-specific fluorescent peptide nucleic acid (PNA) probe. These tests revealed markedly reduced telomere signals in HGPIN lesions when compared to either the surrounding stroma (the supporting framework of an organ typically consisting of connective tissue), or to the stroma and epithelia of adjacent normal-appearing glands. Analysis of the telomere signals in a randomly-selected subset of cases revealed statistically significant telomere shortening in luminal cells (cells lining the prostatic ducts) in nine out of the 11 HGPIN lesions (82 percent) when compared to adjacent normal-appearing prostate luminal epithelial cells. The research suggests that the telomeres of PIN lesions are approximately four-fold shorter than their normal counterparts.
Perhaps most interestingly, the telomere shortening in HGPIN lesions was restricted to the luminal epithelial cells, and did not appear to occur within the basal cell compartment (at the base of the prostatic ducts, directly beneath the luminal cells). When compared to the underlying basal cell layer within the same HGPIN lesions, telomere lengths of the HGPIN luminal cells were statistically significantly shorter than the basal cells in all PIN lesions examined. Since basal cells are thought to produce secretory cells (cells that release functionally specialized secretions), it has been assumed that they are the cells that proliferate and undergo physiological transformations. However, these findings suggest that the luminal cells are not the target for potential cancerous transformation.
"We propose that telomeres are stabilized in the subset of PIN lesions that activate telomerase, and that it is these PIN lesions, theoretically capable of unlimited cell division, that may eventually progress to fully invasive cancer," said Dr. Meeker. "We are currently testing the telomere lengths in several other epithelial cancer precursor lesions to determine whether this phenomenon of early telomere shortening is widespread in other cancers."
In normal cellular activity, cells stop dividing when the telomeres shorten to a certain, pre-determined length; this action is thought to be a normal anti-tumor mechanism present in long-lived organisms. Cancer cells, however, are considered immortal; that is, they will grow indefinitely until stopped, usually by cancer treatments. Cellular immortality is believed to occur, in the majority of cancers, when the normal shortening of telomeres is counter-balanced by activation of the enzyme telomerase, which functions to maintain the lengths of telomeres. This enzyme activity has been detected in 85 percent of all cancer cells - but not in adjacent normal cells.
Founded in 1907, the American Association for Cancer Research (AACR) is a professional society of more than 19,000 laboratory and clinical scientists engaged in cancer research in the United States in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals (Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention).