Telomerase Activity: A Biomarker of Cell Proliferation, Not Malignant Transformation

Abstract

Telomerase activity is readily detected in most cancer biopsies, but not in premalignant lesions or in normal tissue samples with a few exceptions that include germ cells and hemopoietic stem cells. Telomerase activity may, therefore, be a useful biomarker for diagnosis of malignancies and a target for inactivation in chemotherapy or gene therapy. These observations have led to the hypothesis that activation of telomerase may be an important step in tumorigenesis. To test this hypothesis, 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 transitional cell carcinoma (TCC) of the bladder. Our results demonstrated that four of four TCC biopsies, representing both superficial and myoinvasive TCCs, were positive for telomerase activity, but all samples of uncultured HUC were telomerase negative. However, when the same normal HUC samples were established as proliferating cultures in vitro, telomerase activity was readily detected but usually at lower levels than in TCCs. Consistent with the above observation of the telomerase activity in HUCs, telomeres did not shorten during the HUC in vitro lifespan. Demonstration of telomerase in proliferating human epithelial cells in vitro was not restricted to HUCs, because it was also present in prostate and mammary cell cultures. Notably, telomerase activity was relatively low or undetectable in nonproliferating HUC cultures. These data do not support a model in which telomerase is inactive in normal cells and activated during tumorigenic transformation. Rather, these data support a model in which the detection of telomerase in TCC biopsies, but not uncultured HUC samples, ref lects differences in proliferation between tumor and normal cells in vivo.

Cell proliferation, carcinogenesis and diverse mechanisms of telomerase regulation

“…The Ki-S2/ Ki-S5 ratios differed at most fourfold, between 0.2 and 0.8, whereas telomerase levels varied more than 100-fold. Considering the recent suggestion that telomerase activity is not a unique tumor marker but 'only' another marker for cellular proliferation [96], these results indicate that telomerase activity as a prognostic tumor marker has at least a superior diagnostic resolution. In addition to telomere maintenance, the possible involvement of telomerase in DNA repair could make it even more informative in predicting chemoresistance (see below).…”

“…T-lymphocytes from peripheral blood have only low telomerase activity [75][76][77], and some somatic epithelial tissue samples (uroepithelial, breast, prostate) are completely negative [96]. However, telomerase activity drastically increased upon in vitro stimulation of cellular proliferation [77][78][79][80][81]96].…”

Topological–histological investigation of the pterygium

“…It is entirely possible, nevertheless, that during the years of pterygium development the proliferation activity varies. In another very recent study, increased telomerase activity, which serves as a measure of cell proliferation [4], was observed in two-thirds of the pterygia tested [40].…”

Telomerase activity in head and neck tumors after introduction of wild-type p53, p21, p16, and E2F-1 genes by means of recombinant adenovirus

“…However, recent studies by others have demonstrated that telomerase activity is a biomarker of cell proliferation and cell growth rate. 31 Telomerase activity is repressed in cells that exit the cell cycle and become quiescent. 32 Growth suppression and apoptosis could account for the decrease in telomerase activity after Ad5CMV-p53 transduction ( Table 1).…”