Increased tumourigenesis and suppression of acute inflammation by FGFR3 mutation in invasive bladder cancer

Recent reports show that FGFR3 mutations and overexpression are found in a subgroup of muscle invasive bladder cancer with significantly poor prognosis. With an aim to better understand the role of FGFR3 in the invasive bladder cancer, we have examined the process of tumour progression induced by tobacco carcinogen OH-BBN in genetically engineered models that express FGFR3 S249C and K644E mutations in the urothelium.

We found that mice with S249C mutation formed 3.7-fold more tumours comparing to wild-type control. Histopathology of the carcinogen-induced tumours appeared severer in the presence of S249C mutation, indicating that both tumour occurrence and progression were enhanced. The OH-BBN also induced acute inflammatory response in the bladder with high levels of neutrophils infiltrations. Interestingly, a transient suppression of neutrophil recruitment towards the urothelium and the underlying stroma was observed in the presence of FGFR3 S249C at 2 weeks from the start of carcinogen treatment. Immune cell infiltrations, including that of neutrophils, were also observed in the bladders and tumours at 20 weeks, long after the carcinogen induction had ceased. The increased levels of infiltration were correlated according to the level of tumour progression and is unlikely to be controlled by FGFR3 mutations at this stage. Tumour pathogenesis and inflammatory responses in S249C and K644E models were distinct, which may indicate differential regulation of FGFR3 functions by these mutations.

These results suggest that suppression of acute inflammatory response in the bladder may compromise the effective elimination of tumour cells, leading to enhanced tumorigenesis at a later stage. The study provides a novel insight to the tumour-promoting effects of FGFR3 mutations in bladder cancer.