FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

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FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. / Foth, Mona; Ismail, Nur Faezah Binti; Kung, Jeng Sum Charmaine; Tomlinson, Darren; Knowles, Margaret A.; Eriksson, Pontus; Sjödahl, Gottfrid; Salmond, Jonathan M.; Sansom, Owen J.; Iwata, Tomoko.

In: Journal of Pathology, Vol. 246, No. 3, 2018, p. 331-343.

Research output: Contribution to journalArticle

Harvard

Foth, M, Ismail, NFB, Kung, JSC, Tomlinson, D, Knowles, MA, Eriksson, P, Sjödahl, G, Salmond, JM, Sansom, OJ & Iwata, T 2018, 'FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation', Journal of Pathology, vol. 246, no. 3, pp. 331-343. https://doi.org/10.1002/path.5143

APA

Foth, M., Ismail, N. F. B., Kung, J. S. C., Tomlinson, D., Knowles, M. A., Eriksson, P., ... Iwata, T. (2018). FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. Journal of Pathology, 246(3), 331-343. https://doi.org/10.1002/path.5143

CBE

Foth M, Ismail NFB, Kung JSC, Tomlinson D, Knowles MA, Eriksson P, Sjödahl G, Salmond JM, Sansom OJ, Iwata T. 2018. FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. Journal of Pathology. 246(3):331-343. https://doi.org/10.1002/path.5143

MLA

Vancouver

Author

Foth, Mona ; Ismail, Nur Faezah Binti ; Kung, Jeng Sum Charmaine ; Tomlinson, Darren ; Knowles, Margaret A. ; Eriksson, Pontus ; Sjödahl, Gottfrid ; Salmond, Jonathan M. ; Sansom, Owen J. ; Iwata, Tomoko. / FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. In: Journal of Pathology. 2018 ; Vol. 246, No. 3. pp. 331-343.

RIS

TY - JOUR

T1 - FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

AU - Foth, Mona

AU - Ismail, Nur Faezah Binti

AU - Kung, Jeng Sum Charmaine

AU - Tomlinson, Darren

AU - Knowles, Margaret A.

AU - Eriksson, Pontus

AU - Sjödahl, Gottfrid

AU - Salmond, Jonathan M.

AU - Sansom, Owen J.

AU - Iwata, Tomoko

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - cancer immunology

KW - comparative pathology

KW - fibroblast growth factors

KW - inflammation

KW - neutrophils

KW - transgenic mouse model

KW - transitional cell carcinoma

U2 - 10.1002/path.5143

DO - 10.1002/path.5143

M3 - Article

VL - 246

SP - 331

EP - 343

JO - Journal of Pathology

T2 - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 3

ER -