Recent advances in telomere biology: implications for human cancer

Abstract

Research into the basic biology of telomeres continues to reveal details relevant to fundamental aspects of human cancer. The goal of this review is to highlight discoveries made within the last year, with emphasis on their relevance to cancer prevention, diagnosis, prognostics, and treatment. Increasing evidence indicates that dysfunctional telomeres likely play a causal role in the process of malignant transformation, in at least a fraction of human cancers, by initiating chromosomal instability. Telomeres form protective capping structures composed of telomeric DNA complexed with a multitude of associated proteins, the loss of which can have profound effects on telomeric stability. Critical telomeric shortening can lead to telomere "uncapping" and may occur at the earliest recognizable stages of malignant transformation in epithelial tissues. The widespread activation of the telomere synthesizing enzyme telomerase in human cancers not only confers unlimited replicative potential but also prevents intolerable levels of chromosomal instability. Several details regarding telomere structure and telomerase regulation have recently been elucidated, providing new targets for therapeutic exploitation. Various therapeutic strategies aimed at either telomerase or its telomeric substrate are showing promise and may synergize with established anti-cancer agents. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase may possess additional functions, beyond telomere maintenance, that support the growth and survival of tumor cells. Substantial progress has been made in understanding the complex relationships that exist between telomeres and cancer. However, important issues, such as transient activation of telomerase in normal cells and the potential for tumor cell immortalization via telomerase independent means, remain to be clarified.