title: Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance.
abstract: 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. 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. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, 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.
authors.affiliation: 1] Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [2] Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Antonina V
authors.initials: AV
authors.lastname: Kurtova
authors.affiliation: Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Dan L Duncan Cancer Center and Center for Cell Gene &Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Senthil
authors.initials: S
authors.lastname: Pazhanisamy
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Krasnow
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.affiliation: Dan L Duncan Cancer Center and Center for Cell Gene &Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: 1] Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [2] Summer Medical and Research Training (SMART) Program, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Terrence T
authors.initials: TT
authors.lastname: Roh
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Lay
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Philip Levy
authors.initials: PL
authors.lastname: Ho
authors.affiliation: 1] Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [2] Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [3] Dan L Duncan Cancer Center and Center for Cell Gene &Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [4] Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Keith Syson
authors.initials: KS
authors.lastname: Chan
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014945:Wound Healing / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone