Abstract
Recurrent PGE2-induced proliferation of CSCs leads to bladder cancer chemoresistance.
Major finding: Recurrent PGE2-induced proliferation of CSCs leads to bladder cancer chemoresistance.
Mechanism: Chemotherapy-induced apoptosis stimulates a PGE2/COX2 wound-healing response and CSC repopulation.
Impact: Early PGE2/COX2 inhibition during cytotoxic chemotherapy abrogates bladder cancer chemoresistance.
Many advanced carcinomas, including bladder urothelial carcinomas, are treated using multiple cycles of cytotoxic chemotherapy aimed at killing unsynchronized proliferating cancer cells while allowing normal tissues to recover between cycles. However, over time, a subset of patients progressively becomes unresponsive due to repopulation of cancer stem cells (CSC) that have a survival advantage. Using bladder carcinoma xenografts, Kurtova and colleagues found that gemcitabine/cisplatin chemotherapy treatment resulted in enrichment of undifferentiated cytokeratin 14–positive (CK14+) cancer cells with sphere-forming and tumorigenic potential, consistent with a CSC survival advantage. Unexpectedly, these CK14+ cancer cells actively proliferated in response to chemotherapy-induced apoptosis in vitro. These findings were validated in vivo via pulse-chase double labeling, revealing that quiescent label-retaining CK14+ cancer cells were actively recruited to undergo cell division after chemotherapy treatment. Mechanistically, the hormone-like lipid prostaglandin E2 (PGE2) and the enzyme that mediates PGE2 production, cyclooxygenase-2 (COX2), were increased in response to chemotherapy-induced apoptosis of proliferative cells, which stimulated neighboring CK14+ cancer cells to repopulate residual tumors. PGE2-containing supernatant from chemotherapy-treated cells induced sphere formation of CSCs, whereas a PGE2-neutralizing antibody and the COX2 inhibitor celecoxib reduced sphere formation. Furthermore, combination treatment with celecoxib and chemotherapy reduced the expansion of CK14+ cancer cells, enhanced responsiveness to successive chemotherapy treatment cycles, and diminished metastasis to the lung in mice harboring advanced bladder cancer xenografts, including a primary tumor derived from a patient who was resistant to chemotherapy. In addition, expression profiling of chemoresistant bladder carcinomas demonstrated a wound-response gene signature, including upregulation of COX2, which was abolished by combination treatment with celecoxib. Together, these findings highlight a mechanism of progressive chemoresistance in which CSCs actively proliferate upon recurrent cytotoxic chemotherapy treatment, reminiscent of wound-healing responses, and suggest that inhibition of PGE2/COX2 signaling may abrogate tumor repopulation.
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