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 survival1–3. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to re-populate 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 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.

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

“…In this study, we found that UBC stemness is enhanced during chemotherapy with GEM in vivo, evidenced by the increased levels of CSC markers, such as CK14, CK5 and CD44. This is consistent with the observation that cytotoxic chemotherapy induced CK14+ cancer cell proliferation despite reducing tumor size at initial chemotherapy cycle (29). Based on the data from both in vitro and in vivo experiments, we propose that TGFβ1 is upregulated by GEM treatment, and the TGFβ1-mediated dysregulation of the lncRNA-LET/NF90/miR-145 axis promotes cancer cell stemness in residual tumors and subsequently results in chemoresistance (Fig.…”

A fate worse than death: apoptosis as an oncogenic process

“…Tumour repopulation in a mouse xenograft model of breast cancer is promoted in a caspase-3 and iPLA 2 dependent manner, likely through the production of PGE 2 42 . In bladder cancer, production of PGE 2 by apoptotic tumour cells promotes chemoresistance by stimulating cancer stem cell proliferation 43 . The therapeutic relevance of targeting apoptosis-induced proliferation is supported by the finding that neutralisation of PGE 2 signalling reduced the emergence of chemoresistance in a model of human bladder cancer 43 .…”

“…In bladder cancer, production of PGE 2 by apoptotic tumour cells promotes chemoresistance by stimulating cancer stem cell proliferation 43 . The therapeutic relevance of targeting apoptosis-induced proliferation is supported by the finding that neutralisation of PGE 2 signalling reduced the emergence of chemoresistance in a model of human bladder cancer 43 . Importantly, PGE 2 has pleiotropic functions, for example, not only does it promote proliferation, but it can also serve to skew immune responses towards a tumour-promoting, anti-inflammatory phenotype 44 .…”

“…Moreover, caspase inhibitors can completely block extrinsic apoptosis and are thereby unsuitable when this is expected to exert a therapeutic benefit. Another strategy might be to target specific, caspase-dependent effects, for example by blocking the activity of PGE 2 generated by apoptotic cells, using inhibitors such as celecoxib 43 .…”

Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma

“…Tumor repopulation is a phenomenon that has not been well studied in MPM; it is often overlooked due to current customized experimental study strategies. Therefore, new therapeutic options to abrogate tumor repopulation will provide new avenues to improve chemotherapeutic response and clinical outcome (33).…”