FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

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. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

“…Inflammatory response was recently described in a similar BBN mouse model where acute response via neutrophils was shown to be dependent on FGFR3 signaling in a study by Foth et al In agreement with them, we observe similar histological changes at 2 weeks, however, at 20 weeks we observe a slightly more advanced tumor stage, which is probably due to a 2-week longer BBN treatment. When compared to an acute 2-week response, they demonstrate a decrease in neutrophil infiltration, after a 10 week-BBN treatment, which is in accordance with an overall decrease in inflammatory response described in our study [36]. Our histological findings are further supported by a decrease in the expression of major inflammatory cytokines and chemokines that are well-described drivers in the setups of acute and chronic inflammation.…”

Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

“…In telomerase-immortalized human urothelial cells (TERT-NHUC) expressing the FGFR3–TACC3 fusion gene, a point mutation in FGFR3 (S249C) activates the MAPK pathway and phospholipase cγ1 (PLCγ1), and induces PLCγ1-dependent overgrowth at the confluence ( 28 , 29 ). At the same time, other studies have shown that a FGFR3 mutation suppressed acute inflammation, causing immune cells (mainly neutrophils) to behave aberrantly in tumors, thereby causing tumor progression ( 30 ). The high-frequency mutations of FGFR3 in the C3 and C4 subtypes are likely to be the cause of poor prognosis.…”

FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice

“…In addition, some studies also showed the potential roles of FGFR3 in the regulation of inflammatory response under certain conditions. FGFR3 mutation could increase tumourigenesis by suppressing acute inflammation 19. Moreover, fibroblast growth factor 9 (FGF9), a high-affinity ligand of FGFR3, could decrease monocyte infiltration and increase M2 macrophage differentiation in the post-myocardial infarction diabetic heart model 20.…”