Telomerase in cancer: Clinical applications

Abstract

The biology of telomeres and telomerase has been the subject of intensive investigative effort since it became evident that they play a significant role in two important biological processes, the loss of cellular replicative capacity inherent to organismal ageing and the unrestricted cell proliferation characteristic of carcinogenesis. Telomere shortening in normal cells is a result of DNA replication events, and reduction beyond a critical length is a signal for cellular senescence. One of the cellular mechanisms used to overcome proliferative restriction is the activation of the enzyme telomerase, which replaces the loss of telomeric DNA that occurs at each cell division. Studies have demonstrated that tumours have shorter telomeres than normal tissue and that telomerase is activated in up to 90% of all human cancers while it is present only in a limited range of normal adult tissues. The role of telomerase in the extension of the cellular replicative lifespan has recently been shown by ectopic expression of the enzyme, being consistent with the oncogenesis model whereby the acquisition of an 'immortal' phenotype is a requirement for advanced tumour progression. In this article we review the present knowledge of telomeres and telomerase in cancer and discuss the potential use of this enzyme as a diagnostic and prognostic tumour marker and as a target for cancer therapy.

Cell proliferation, carcinogenesis and diverse mechanisms of telomerase regulation

“…Initial reports of a similar correlation in gastric cancer [120,121] were questioned later [122]. More details are available in recent reviews by Urquidi et al [123], Shay [124], McKenzi [125], in special issues of the European Journal of Cancer [31] and of Biochemistry (Moscow) [32], and in several books [33,34]. Further evaluation of telomerase activity as a novel tumor marker should be based on the comparison with other established markers in tumor diagnostics, such as determination of the fraction of actively proliferating cells in tumor biopsies.…”

Telomerase Activity Is Increased and Telomere Length Shortened in T Cells from Blood of Patients with Atopic Dermatitis and Psoriasis

“…The concept at the moment is that germline cells or immature cells have increased telomerase activity and long telomeres, whereas somatic cells have low or no telomerase activity and normal telomere length. Malignant cells have increased telomerase activity and short telomere length (12,13).…”

Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954

“…Telomerase activation is considered to be a critical step in cancer progression due to its role in cellular immortalization. The level and frequency of telomerase activity and component gene expression in cancers when compared to normal cells makes telomerase an attractive target for anticancer strategies (Nowak and Chrapusta, 1998;Sharma et al, 1997;Shay et al, 2001;Urquidi et al, 1998;White et al, 2001;Yi et al, 1999). Indeed, the inhibition of telomerase in cancer cells in tissue culture can lead to cell death, strongly supporting the e orts to develop telomerase inhibitors for clinical use (White et al, 2001).…”