FGFR3 mutation increases bladder tumorigenesis by suppressing acute inflammation

Foth, M., Ismail, N. F. B., Kung, J. S. C., Tomlinson, D., Knowles, M. A., Eriksson, P., Sjödahl, G., Salmond, J. M., Sansom, O. J. and Iwata, T. (2018) FGFR3 mutation increases bladder tumorigenesis by suppressing acute inflammation. Journal of Pathology, 246(3), pp. 331-343. (doi: 10.1002/path.5143) (PMID:30043421) (PMCID:PMC6334176)

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 Wildtype 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.

• Item Type: Articles
• Additional Information: This work was funded by University of Glasgow MRC Centenary Award (MF), JPA Public Service Department of Malaysia (NFBI), Pathological Society of Great Britain and Ireland, Wellcome Trust (JSCK), Beatson Endowment Fund (JMS) and Cancer Research UK A21139, A12481 and A17196 (OJS).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Iwata, Dr Tomoko and Sansom, Professor Owen and Salmond, Dr Jonathan and ISMAIL, NUR FAEZAH BINTI
• Authors: Foth, M., Ismail, N. F. B., Kung, J. S. C., Tomlinson, D., Knowles, M. A., Eriksson, P., Sjödahl, G., Salmond, J. M., Sansom, O. J., and Iwata, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Journal of Pathology
• Publisher: Wiley
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 25 July 2018
• Copyright Holders: Copyright © 2018 Pathological Society of Great Britain and Ireland
• First Published: First published in Journal of Pathology 246(3): 331-343
• Publisher Policy: Reproduced in accordance with the publisher copyright policy