TELOMERASE ACTIVITY - A BIOMARKER OF CELL-PROLIFERATION, NOT MALIGNANT TRANSFORMATION

Telomerase activity is readily detected in most cancer biopsies, but n ot in premalignant lesions or in normal tissue samples with a few exce ptions that include germ cells and hemopoietic stem cells. Telomerase activity may, therefore, be a useful biomarker for diagnosis of malign ancies and a target for inactivation in chemotherapy or gene therapy. These observations have led to the hypothesis that activation of telom erase may be an important step in tumorigenesis. To test this hypothes is, we studied telomerase activity In Isogeneic samples of uncultured and cultured specimens of normal human uroepithelial cells (HUCs) and in uncultured and cultured biopsies of superficial and myoinvasive tra nsitional cell carcinoma (TCC) of the bladder. Our results demonstrate d that four of four TCC biopsies, representing both superficial and my oinvasive TCCs, were positive for telomerase activity, but all samples of uncultured HUC were telomerase negative. However, when the same no rmal HUC samples were established as proliferating cultures in vitro, telomerase activity was readily detected but usually al lower levels t han in TCCs. Consistent with the above observation of the telomerase a ctivity in HUCs, telomeres did not shorten during the HUC in vitro lif espan. Demonstration of telomerase In proliferating human epithelial c ells in vitro was not restricted to HUCs, because it was also present in prostate and mammary cell cultures. Notably, telomerase activity wa s relatively low or undetectable in nonproliferating HUC cultures. The se data do not support a model in which telomerase is inactive in norm al cells and activated during tumorigenic transformation. Rather, thes e data support a model In which the detection of telomerase in TCC bio psies, but not uncultured HUC samples, reflects differences in prolife ration between tumor and normal cells in vivo.