Abstract

Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.

Highlights

  • Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis

  • Using CD44+/CD24−/ESA+ as breast CSC cell surface markers, the percentage of putative CSCs in MCF7 monolayer ranged from 0.34% to 0.82% of the total cell population (Fig. 1B)

  • 106 of 248 (42.7%) single cells from MCF7 mammosphere cultures were clonogenic (Fig. 1D; Fisher's exact test, P < 0.0001). This is consistent with cell surface marker measurements showing that the percentage of CSCs from the MCF7 line was greater in mammospheres than in monolayer culture

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Summary

Introduction

Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Inhibition of telomerase has been shown to limit the growth of cancer cells in multiple tumor types [16,17,18,19] Both bulk cancer cells and CSCs express telomerase, the level of telomerase activity and/or the telomere length observed in CSCs relative to their bulk tumor counterpart have been reported to vary with tissue type [4, 20,21,22]. It has been suggested that CSCs could be sensitive to telomerase-based therapy [23]

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