Role of telomeres and telomerase in cancer

Abstract

There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer. Normal human cells progressively lose telomeres with each cell division until a few short telomeres become uncapped leading to a growth arrest known as replicative aging. In the absence of genomic alterations these cells do not die but remain quiescent producing a different constellation of proteins compared to young quiescent cells. Upon specific genetic and epigenetic alterations, normal human cells bypass replicative senescence and continue to proliferate until many telomere ends become uncapped leading to a phenomenon known as crisis. In crisis cells have critically shortened telomeres but continue to attempt to divide leading to significant cell death (apoptosis) and progressive genomic instability. Rarely, a human cell escapes crisis and these cells almost universally express the ribonucleoprotein, telomerase, and maintain stable but short telomeres. The activation of telomerase may be thought of as a mechanism to slow down the rate genomic instability due to dysfunctional telomeres. While telomerase does not drive the oncogenic process, it is permissive and required for the sustain growth of most advanced cancers. Since telomerase is not expressed in most normal human cells, this has led to the development of targeted telomerase cancer therapeutic approaches that are presently in advanced clinical trials.

Fig. 1

Certain male reproductive cells and embryonic stem cells retain full or almost full telomere length due to expression of telomerase activity. Pluripotent stem cells have regulated telomerase activity and thus they lose telomeres throughout life but at a reduced rate. Most somatic cell do not express telomerase activity and thus lose telomere length with each division at a faster rate until the cells uncap a few of their telomeres and undergo a growth arrest called replicative senescence. In the absence of cell cycle checkpoints (e.g. p53/pRB pathway), cells bypass senescence until they reach crisis. In crisis telomeres are so short that chromosome end fusions occur and there is increased genomic instability (probably due to chromosomal, breakage, fusion, bridge cycles). A rare cell that escapes crisis almost universally does so by reactivating telomerase and this cell can now become a cancer cell with limitless potential to divide. Almost all cancer cells have short telomeres and thus inhibitors of telomerase should drive such cancer cells into apoptotic cell death.

Fig. 2

While most tumor specimens have short telomeres there is heterogeneity such that some cells may have slightly longer telomeres than others. After standard radiotherapy or chemotherapy a subset of residual cancer cells often regrow and become resistant to the initial therapy. In this setting, adding a telomerase inhibitor in the maintenance or consolidation phase of treatment may prolong progression free survival. Clinical trials are in progress to test this idea in humans with non small cell lung cancer following standard doublet chemotherapy.