Expression of the telomerase catalytic subunit, hTERT, induces resistance to transforming growth factor b

n indefinite lifespan is one of the most common tumor-associated properties and is likely crucial for malignantprogression, because tumor cells may need to overcome theproliferative constraints imposed by senescence to accumulatethe multiple errors necessary for invasive and metastatic behav-ior. The finite lifespan of normal human somatic cells is thoughtto be due to their lack of telomerase activity, resulting incontinued telomere shortening with cell division. In contrast,human tumor tissues frequently contain cells that display anindefinite lifespan in culture, and most human carcinomasexpress high telomerase activity, which allows the telomeric endsof linear chromosomes to be maintained (1). Tumor-derivedcells contain many other cellular derangements, includingchanges in expression of tumor suppressor genes, protoonco-genes, genomic instability, acquisition of growth factor andanchorage independent growth (AIG), and alterations in cell-cycle regulatory proteins. In cancers derived from epithelialcells, malignancy is commonly correlated with a loss or reductionin the ability of the multifunctional cytokine transforminggrowth factor b(TGF-b) to inhibit growth (2).Whether acquisition of telomerase activity and immortalitysimply confer a greater time frame for accumulation of tumor-promoting errors, or intrinsically contribute to cancer formation,has not been determined. Previously, it was not possible to separateimmortal from malignancy-associated properties due to the obli-gate derivation of immortal cells from tumors or abnormal tissues,orbycellexposuretoviraloncogenesorphysicalcarcinogens.Morerecently, finite lifespan cells exposed to the human catalytic subunitof the telomerase complex, hTERT, have been rendered immortal(3), making it possible to determine whether hTERT-inducedimmortality confers other alterations in cellular growth control.Initial published reports on hTERT-immortalized human cellsshowed no alterations in growth control in response to serumdeprivation, high cell density, specific pharmacological inhibitors,or oncogenic ras, nor were gross chromosome instability, AIG, ortumorigenicity reported (4–6). However, ectopic hTERT expres-sion in conjunction with ectopic expression of the oncogenes