4 Telomerase and Human Cancer

Abstract

The continuous growth of advanced human carcinomas almost universally correlates with the up-regulation of telomerase. As such, telomerase is a very attractive target for cancer therapeutics. Although the role of telomerase in cell immortalization is well established, it is less clear whether the expression of telomerase in cancer is simply a passive component of the neoplastic process, a critical requirement for stabilizing the genome to prevent catastrophic genomic instability, or a fundamental carcinogenic mechanism enhancing genomic instability. These concepts and several other key issues still remain to be resolved and are discussed in this chapter. In addition, the pros and cons of the most promising antitelomerase approaches currently being investigated are reviewed.

BACKGROUND
The ends of human chromosomes (telomeres) are composed of thousands of TTAGGG DNA repetitive sequences. Telomerase is a ribonucleoprotein enzyme complex (a cellular reverse transcriptase) that maintains telomere length in cancer cells by adding TTAGGG repeats onto the telomeric ends, thus compensating for the normal erosion of telomeres that occurs in all dividing cells. Telomerase is expressed during early development and remains fully active in specific germ-line cells, but it is undetectable in most normal somatic cells except for proliferative cells of renewal tissues (e.g., bone marrow cells, basal cells of the epidermis, proliferative endometrium, and intestinal crypt cells). In all nonreproductive proliferative cells, progressive telomere shortening is observed, and when telomeres become sufficiently short, further cell division is blocked, a process often referred to as replicative senescence (Harley et al. 1990). Telomere shortening is the molecular...