Foth, M, Ismail, NFB, Kung, JSC et al. (7 more authors) (2018) FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. Journal of Pathology, 246 (3). pp. 331-343. ISSN 0022-3417
Abstract
Recent studies of muscle‐invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH‐BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH‐BBN‐driven tumours were increased in the presence of an S249C mutation compared to wild‐type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH‐BBN‐treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early‐phase neutrophil depletion using an anti‐Ly6G monoclonal antibody resulted in an increased neutrophil‐to‐lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3‐dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour‐promoting effect of FGFR3 mutations via regulation of inflammation at the pre‐tumour stage in the bladder.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited. |
Keywords: | transitional cell carcinoma; transgenic mouse model; fibroblast growth factors; cancer immunology; neutrophils; inflammation; comparative pathology |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Oncology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Section of Experimental Oncology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 27 Jul 2018 12:51 |
Last Modified: | 25 Jul 2019 00:42 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/path.5143 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:133868 |
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