Telomeres and telomerase in normal and cancer stem cells

Abstract

Differences between normal adult tissue stem cells and cancer stem/initiating cells remain poorly defined. For example, it is controversial if cancer stem cells can become fully quiescent, require a stem cell niche, are better at repairing DNA damage than the bulk of the cancer cells, and if and how they regulate symmetric versus asymmetric cell divisions. This minireview will not only provide our personal views to address some of these outstanding questions, but also present evidence that an understanding of telomere dynamics and telomerase activity in normal and cancer stem cells may provide additional insights into how tumors are initiated, and how they should be monitored and treated.

Fig. 1

The M1 and M2 model of senescence and crisis. All normal human somatic cells have progressive shortening of telomeres with each cell division. This is also true in proliferative (transit amplifying) adult stem cells. When a few telomeres in a cell reach a shortened state, a DNA damage signal is initiated. This DNA damage signal indicates that the shortened telomeres is being sensed as uncapped or broken DNA. In cells that have bypassed the M1 senescent state by inactivation of important cell cycle checkpoint genes (e.g. TP53 and/or pRB), cells ignore the ongoing DNA damage signal and continue to divide until many telomeres are critically shortened. During this extended lifespan period, end associations occur eventually leading to breakage-fusion-bridge cycles resulting in M2 or a state of crisis. During crisis apoptotic cell death almost universally occurs. However, in a rare human cell (based on fluctuation analyses calculated to be about one in ten million cells) an immortalization event occurs. This cell has two characteristics, expression of telomerase and stabilization of telomeres.

Fig. 2

Changes in telomere length in germline cells, normal stem cells and preneoplastic somatic cells. Telomeres progressively shortening in normal stem and preneoplastic cells but not in proliferating male germline spermatocytes. When telomeres are very short in preneoplastic cells, a rare cell stabilizes its telomeres by upregulating or reactivating telomerase. This cell is likely to initially have very short telomeres and telomerase may be a mechanism to reduce the ongoing genomic instability that occurs when cells are in crisis at the time of immortalization. Thus, the bulk of tumor cells including cancer stem cells have much shorter telomeres compared to germline or normal stem cells. Robust telomerase inhibitors currently in clinical trials are likely to induce apoptosis in cancer cells before adversely affecting normal stem cell functions.

Fig. 3

Hypothetical model for retention of template immortal DNA strand in cancer stem cells. Similarly to a proposed mechanism that may exist in certain adult stem cells, it is possible that the cancer initiating/stem cell have engaged a mechanism to retain specific characteristics of stem cells. Perhaps due to distinct epigenetic marks at centromeric DNA as well as at specific genomic sites, specific cancer cells (which are not quiescent, express telomerase, and have shortened telomeres), may preferentially retain the template immortal strand and the parental centriole in the cancer stem cell while the newly replicated DNA strands may segregate with the cancer committed or more differentiated cells. While this would help explain the rare nature of cancer stem cells, currently there is a lack of experimental support.