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.

Immortalisation of Normal Human Urothelial Cells Compromises Differentiation Capacity

“…The demonstration of endogenous/basal hTERT by NHU cells was in agreement with previous reports [23]. hTERT activity was also confirmed by assaying telomerase activity (Table 1).…”

“…Proliferating NHU cells express (low level) endogenous hTERT expression, as shown in this study ( Figure 1C) and elsewhere [23], as do some somatic cell types that have the capacity to switch from a quiescent to highly-proliferative phenotype. Urothelium is renowned as a low-turnover, mitotically-quiescent epithelium that has high regenerative capacity.…”

Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up

“…Activation of this enzyme enables cells to overcome replicative senescence and divide indefinitely. 18,19 Telomerase activity is considered a marker of cell proliferation, 20 as it is present in normal tissues that are highly proliferative, such as oral mucosa, 21 the basal layer of epidermis, 22 and proliferative-phase endometrium. 23 Telomerase activity is also present in a high percentage of human tumor types.…”

“…23 Telomerase activity is also present in a high percentage of human tumor types. 24 In malignancies, telomerase activity may simply mirror the fraction of proliferating cells; 20 however, it is also hypothesized that tumor cells may independently upregulate telomerase levels. 25 Studies have revealed that there are two major subunits contributing to in vitro activity of the telomerase enzyme complex: an intrinsic RNA component (TERC) containing a template region that binds to telomeric repeats; and a catalytic subunit with reverse transcriptase activity (TERT).…”

Induction of telomerase activity in v-myc-transformed avian cells

“…It has been proposed that telomerase activity correlates with cell proliferation (Belair et al, 1997) and that, within telomerase-positive cells, is differentially expressed during the cell cycle (Holt et al, 1996). Furthermore, the amount of the RNA component of the telomerase holoenzyme, but not its enzymatic activity, correlates in mouse mammary tumors with the level of histone H4 mRNA, a proliferative marker (Broccoli et al, 1996).…”