The significance of telomerase activation and cellular immortalization in human cancer.

Repression of telomerase in the somatic tissues of humans, and probably other long-lived mammals, appears to have evolved as a powerful protective barrier against cancer. Immortalization in vitro of normal human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. Inactivation of the effectors of replicative senescence, i.e. genes encoding one or more elements of the p16/pRB and/or ARF/p53/p21 anti-proliferative pathways, is required for telomerase depression leading to immortalization. Regulation of telomerase in normal human cells is mediated primarily by transcriptional repression of hTERT, the gene encoding the catalytic subunit of telomerase. Rodent cells do not possess stringent controls on telomerase activity in the soma and this explains why they are so readily immortalized and transformed in culture compared with their human counterparts. Because active telomerase has been found to exist in the proliferative compartments of self-renewing tissues, it is not yet clear whether the telomerase present in 90% of human cancers exists as a consequence of selection of pre-existing telomerase-positive cells during carcinogenesis or through induction of hTERT expression in cells in which it is normally tightly repressed. In support of the latter, chromosome transfer techniques have revealed the presence of genes on normal human chromosomes that are able to extinguish hTERT transcription in cancer cells and induce them to undergo senescence. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and malignant progression. Telomerase therefore represents an attractive target at which to aim new anti-cancer drugs. Results with a variety of telomerase inhibitory strategies in human cancer cells have confirmed that its functional inactivation results in progressive telomere shortening, leading to growth arrest and/or cell death through apoptosis. Promising candidate small molecule inhibitors are beginning to emerge that will form the basis for anti-telomerase drug development.