Question

Why is a drug that inhibits telomerase not a good choice for cancer therapy? Make sure to explain what telomerase does in a normal healthy cell.

Answer 1

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model.

Telomerase in stem cells

Normal tissue stem cells reside in microenvironmental niches that are tissues/organ specific. Stem cells are negative for differentiation markers, are not actively cycling in vivo, and generally form large self-renewing colonies in vitro. Thus, there are many differences between normal stem cells in vivo and in vitro. The function of stem cells appears to change with increased age and this may be due in part to progressive telomere shortening. Stem cells also show progressive shortening of telomeres with increased age, while embryonic stem cells appear to fully maintain telomeres. This is believed to be due to fully active telomerase in embryonic stem cells that does not occur in stem cells of renewal tissues . Thus, while proliferative descendents of normal stem cells have detectable telomerase activity, this activity is rarely sufficient to fully maintain telomere length . Very little is known about the regulation of telomerase in proliferative stem cells. Thus, a major difference between normal tissue stem cells and cancer cells is that in the latter but not the former, stable telomere length are maintained. Normal tissue stem cells show progressive telomere shortening with increased age and telomerase is carefully regulated so that it is not continuously expressed. Thus, normal tissue stem cells are telomerase competent but mostly silent, while cancer cells are almost universally telomerase expressing. There are no apriori reasons to assume that subsets of cancer cells (e.g. cancer stem cells) would maintain their telomeres differently from the bulk of the tumor, even though there are frequent comparisons made between normal stem cells and cancer stem cells as if cancer stem cells are simply derivatives of normal stem cells. This has led to many misconceptions that persist in the general scientific thought collective. Many of these comparisons are based on very marginal data and will be discussed further. Importantly, cancer cells expressing telomerase and forced to differentiate or to become quiescent, either undergo apoptosis or down regulate telomerase suggesting that part of becoming a cancer cell may be the inability to efficiently undergo quiescence as do normal tissue stem cells. Cancer cells may lack the cell cycle checkpoint activities that allow them to completely growth arrest or there may not be a cancer specific niche as occurs in normal stem cells to allow cancer stem cells to become completely quiescent.

Review of telomerase in cancer stem cells

Embryonic stem cells derived early in embryogenesis, are believed to proliferate by equal division where the two daughter cells produced by the division share the same stem cell characteristics. Later during organogenesis, tissue stem cells are believed to divide by unequal division where the two daughter cells differ in their characteristics such than one remains a stem cell and the other becomes a progenitor or transit amplifying cell. There is robust experimental evidence that progenitor or transit amplifying normal cells express high levels of telomerase while the remaining daughter stem cell rapidly becomes quiescent (e.g. not dividing or very slowly dividing) and does not express telomerase. How does this asymmetric cell division occur? What regulates symmetric cell division in embryonic stem cells but asymmetric cell division in normal tissue stem cells? What regulates telomerase activity in quiescent stem cells versus proliferating transit amplifying cells? While technological advances have made it possible to isolate stem and progenitor cells and there is a beginning description of the molecular characteristic of these various cell types, there is still much we do not know. Clearly the progenitor cells can undergo many divisions to eventually differentiate into the functional cells of the specific tissue but these are almost universally “end” cells that are eventually lost from the tissue after completing their physiological functions. In some tissues there are many levels of transit amplifying cells while in others there are not. The mass of a tissue is maintained by the balance between differentiated cell death and production of new transit amplifying cells. Some tissues turn over rapidly such as in the gastrointestinal tract and thus there is a high number of transit amplifying cells. In the brain there is almost no cell turnover and interestingly, the telomeres of neuronal cells do not change with increased age. The terminally differentiated cells of the brain and mature differentiated gastrointestinal cells also do not express telomerase activity.