Scientists from Baylor College of medicine have identified a new mechanism by which bladder cancer stem cells(CSCs) actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles. It may provide a potential new method to cure cancer. This study was published in Nature.

Bladder urothelial carcinomas contain cells that span various cellular differentiation stages, cytokeratin 14(CK14) marks the most primitive (or least differentiated) cells and patients with abundant Ck14 staining correlate with poor survival. On the other hand, cytotoxic chemotherapy remains the standard of care for many advanced carcinomas. Although chemotherapy is effective in debulking tumour mass, certain patients show initial response but progressively become unresponsive after multiple treatments.

In this study, researchers investigate the unexplored concept that CSCs may actively proliferate in response to chemotherapy-induced damages, similar to how tissue resident stem cells mobilized to wound sites during tissue repair. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E₂ (PGE₂) release paradoxically promotes neighboring CSC repopulation.

This repopulation can be abrogated by a PGE₂ signaling. In vivo administration of the cycooxygenase-2(COX2) inhibitor celecoxib effectively abolishes a PGE₂- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograf tumour, including primary xenografts derived from a patient who was resistant to chemotherapy.

These findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.

Reference:

Kurtova A V, Xiao J, Mo Q, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance[J]. Nature, 2014.