The role of telomere length and telomerase activity in cell immortalization and tumourigenesis

Abstract

<p>Human somatic cells have a finite lifespan. In contrast, since most cancers evolve through expansions of mutant clones with increasingly more transformed phenotypes, tomour cells may exhaust the proliferative potential of normal cells and possibly acquire an unlimited replicative capacity (immortality). Thus, one essential step in tumourigenesis may be the acquisition of an immortal phenotype. The results presented in this thesis suggest that telomeres, the terminal structures that prevent illegitimate recombination and ensure the proper segregation of chromosomes, and telomerase, the enzyme that elongates telomeres de novo, play critical roles in the process of immortalization of transformed cells both in tissue culture and in vivo.</p> <p>In a tissue culture model of transformation we have shown that telomeres shorten as normal cells divided, as previously reported (Harley et al., 1990), and that, consistent with this observation, the cells lacked detectable levels of telomerase activity. Cells that were driven to divide beyond their normal lifespan by transformation with viral oncogenes did not directly acquire telomerase activity; consequently telemeres continued to shorten until a proliferative crisis, characterized by cell death, was reached. At crisis, chromosome ends contained very little telomeric DNA and appeared to be unstable since the frequency of dicentric chromosomes, aberrations that can be formed by the fusion of chromosome ends, increased. These data suggest that the critically short telomeres detected at crisis may no longer be functional, resulting in genomic instability and potentially cell death. Immortal clones which survived crisis maintained short, but stable telomeres and had telomerase activity. Similarly, malignant cells from the advanced stages of different cancers also had short telomeres and were telomerase positive. Moreover, in one cancer analyzed, the telomeres of malignant cells were found to be stably maintained in vitro and in vivo. These data, although correlative in nature, strongly suggest that, in culture as well as in vivo, telomerase must be activated to counter the lethal loss of telomeric DNA if cells are to become immortal.</p>