Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance

Using human bladder cancer xenograft models, a new mechanism involving an active proliferative response of cancer stem cells to chemotherapy-induced damage is shown, driven by prostaglandin E 2 (PGE 2 ) release in a manner similar to PGE 2 -induced wound repair; pharmacological inhibition of the PGE 2 /COX2 axis by celecoxib attenuates chemoresistance, suggesting a possible adjunctive therapy for bladder carcinomas. Cancer stem cells' role in chemoresistance Recent studies demonstrated that cancer stem cells (CSCs) have a survival advantage in response to chemotherapy. Here Antonina Kurtova and colleagues we investigate the idea that CSCs may actively proliferate in response to chemotherapy-induced damage in a manner analogous to the stem cell mobilization seen at wound sites during tissue repair. The authors show in bladder cancer models in mice, including patient-derived xenografts, that during successive cycles of chemotherapy, stem-cell-like CK14 + cells become enriched and repopulate the tumours in-between cycles. This is driven by prostaglandin E 2 (PGE 2 ) release from dying tumour cells, in a manner akin to PGE 2 -induced wound repair. Combination with an PGE2-neutralizing antibody attenuates chemoresistance and suggests a possible therapeutic strategy for bladder carcinomas. Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival 1 , 2 , 3 . Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. 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 4 , 5 , 6 , 7 . While chemotherapy effectively induces apoptosis, associated prostaglandin E 2 (PGE 2 ) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE 2 -neutralizing antibody and celecoxib drug-mediated blockade of PGE 2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE 2 - and COX2-mediated