"Cancer researchers have debated whether shortened telomeres were a cause or effect of tumors," says Alan K. Meeker, Ph.D., lead author of the study and a postdoctoral fellow in urology and pathology at Hopkins. "What our study suggests is that telomere dysfunction may be a key component in the development of many epithelial cancers, those that arise from tissues lining our organs."
Studying tissue taken from small precancerous lesions in the bladder, esophagus, large intestine, mouth and cervix, the research team found abnormal telomere lengths in 97 percent of the cases examined. In particular, abnormally short telomeres were found in 88 percent of cases.
"We were surprised how often you see shortened telomeres this early in the development of these cancers," says Meeker. "It's a strong indicator that abnormal telomeres are likely playing a causal role in cancer development."
Telomeres cap the chromosome ends, protecting the interior, gene-containing parts of the chromosome from being accidentally lost. As normal cells divide and age, some of the telomere DNA is lost, and the telomeres get progressively shorter. Normal cells monitor the lengths of their telomeres and initiate cell suicide or halt cell division when telomeres get too short. Other researchers have shown in mice that cancer, which is characterized principally by unrestricted cell growth and lack of cell death, can occur if this monitoring system breaks down, leading to the development of chromosomal abnormalities.
"It appears that the telomere shortening frequently observed in large advanced tumors has already occurred before it can be detected by standard diagnostic tools, when cellular changes characteristic of early precancer can only be seen through a microscope by a pathologist," says Angelo M. De Marzo, M.D., Ph.D., senior author of the study and associate professor of urology, pathology and oncology at Johns Hopkins. "Therefore, intervention strategies aimed at preventing, or even reversing, telomere shortening may be effective in lowering cancer incidence. And assessing telomere length may provide a new direction for cancer prevention studies, and lead to improved early diagnosis of precancerous lesions."
For the study, published in the May 15 issue of the journal Clinical Cancer Research, Meeker, De Marzo and colleagues used a technique called fluorescent in situ hybridization (FISH) to compare telomere length in cells from both precancerous lesions and normal surrounding cells of the bladder, esophagus, large intestine, mouth and cervix.
The FISH test uses fluorescent-labeled probes specific for particular locations in DNA and is commonly used to detect or confirm gene or chromosome abnormalities. Chromosomal DNA is first denatured, a process that separates the strands within the DNA's double helix structure. The Hopkins scientists then added a fluorescent probe specific for telomere regions. As the DNA re-forms into a double helix, it blends with the fluorescent molecules, enabling scientists to examine specific chromosomal locations under a microscope for the level of fluorescence that corresponds to telomere length.
Not all precancerous epithethial lesions are capable of fully advancing to malignant cancers, Meeker says. One reason for this may be that if genetic instability gets too high, the cells die, thus blocking cancer progression. Only cells that find a way to balance their telomere length - allowing unlimited cell division and a limited degree of genomic stabilization - can progress to becoming an invasive, life-threatening tumor.
The Hopkins research team examined 35 precancerous lesions from 25 patients, including 11 lesions from eight bladders, three lesions from three uterine cervixes, seven lesions from five large intestines, six lesions from three esophagi and eight lesions from six mouths. They scored the telomere lengths on a five-point scale ranging from very short to very long.
Overall, the group found telomere length abnormalities in 34 of 35 lesions studied (97 percent). Short or very short telomeres were observed in all lesions of the esophagus, large intestine and uterine cervix; in eight of 11 (72 percent) lesions of the bladder; and in seven of eight lesions of the oral cavity, which includes the mouth and throat. Ten of 35 (29 percent) lesions, particularly those of the bladder, displayed a variety of telomere lengths.
More than one million human epithelial cancers are diagnosed every year, Meeker says, and these cancers cause a half-million deaths each year.
Previous studies by the research team and others at Johns Hopkins found shortened telomeres in more than 90 percent of precancerous lesions of the prostate, pancreas and breast.
The current study was funded by the U.S. Public Health Service. Coauthors were Jessica L. Hicks, Christine A. Iacobuzio-Donahue, Elizabeth A. Montgomery, William H. Westra, Theresa Y. Chan and Brigitte M. Ronnett.
Meeker, Alan K., et al, "Telomere Length Abnormalities Occur Early in the Initiation of Epithelial Carcinogenesis," Clinical Cancer Research, May 15, 2004, Vol. 10, Issue 10.
Johns Hopkins Kimmel Cancer Center
Clinical Cancer Research