Editors' ChoiceCancer

Awakening the Beast: Chemotherapeutic Activation of Cancer Stem Cells

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ec3
DOI: 10.1126/scitranslmed.aaa3470

Chemotherapy represents the standard of care for many advanced cancers and works on the principle of killing proliferating cells, many of which are tumor cells. The administration of chemotherapeutic agents occurs in cycles to allow recovery of normal tissue but may also allow for the regrowth of tumor cells. Kurtova and colleagues used a bladder cancer xenograft system to demonstrate that cancer stem cells (CSCs), a population of self-renewing cells resistant to chemotherapy, can be driven to proliferate as a result of chemotherapy.

CSCs are refractory to conventional chemotherapies and share signaling pathways enriched in wound healing, which is a response activated by chemotherapy. On the basis of this relationship, the authors evaluated bladder cancer patients before and after chemotherapy and found that those with greater CSC activation had a poorer prognosis. The authors also assessed the cellular response in patient-derived xenograft models and observed that although chemotherapy was effective at reducing tumor volume, it increased the proliferation of CSCs and induced quiescent CSCs to proliferate. The apoptosis induced by chemotherapy also resulted in a release of factors such as prostaglandin E2 (PGE2), which induced proliferation and self-renewal when applied to CSCs. Targeting PGE2 signaling with blocking antibodies reduced self-renewal, and in vivo inhibition of cyclooxygenase-2 (the enzyme that mediates PGE2 synthesis) by celecoxib attenuated tumor growth and CSC repopulation.

These results highlight the fact that CSCs are not only resistant to chemotherapy, but can also be induced to proliferate as a result of chemotherapy. These findings suggest a need to revisit current clinical paradigms to include treatments that attenuate chemotherapy-induced CSC proliferation by targeting PGE2 via FDA-approved compounds such as celecoxib.

A. V. Kurtova et al. Blocking PGE2-inducted tumor repopulation abrogates bladder cancer chemoresistance. Nature 10.1038/nature14034 (2014). [Abstract]

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