Blocking PGE^sub 2^-induced tumour repopulation abrogates bladder cancer chemoresistance

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...

Full description

Saved in:
Bibliographic Details
Published inNature (London) Vol. 517; no. 7533; p. 209
Main Authors Kurtova, Antonina V, Xiao, Jing, Mo, Qianxing, Pazhanisamy, Senthil, Krasnow, Ross, Lerner, Seth P, Chen, Fengju, Roh, Terrence T, Lay, Erica, Ho, Philip Levy, Chan, Keith Syson
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 08.01.2015
Subjects
Apoptosis
Bladder cancer
Cancer therapies
Cell cycle
Cell division
Chemotherapy
Cytotoxicity
Gene expression
Patients
Proteins
Repopulation
Stem cells
Tumors
Online AccessGet full text

Cover

More Information
Summary: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 survival1-3. 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 repair4-7. While chemotherapy effectively induces apoptosis, associated prostaglandin E^sub 2^ (PGE^sub 2^) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE^sub 2^-neutralizing antibody and celecoxib drug-mediated blockade of PGE^sub 2^ signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE^sub 2^- 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.
ISSN:0028-0836
1476-4687