The roles of Fibroblast Growth Factor 22 in development, tissue repair and homeostasis, and the associated role of FGF signalling in skin cancer.

Abstract

Fibroblast Growth Factors (FGFs) play critical roles during development, tissue homeostasis and repair and in controlling cell proliferation, survival, migration and differentiation. Of the 22 mammalian FGFs, FGF22, a member of the FGF7/10/22 subfamily, is relatively understudied. I have investigated the in vivo functions of FGF22 in mice engineered to lack Fgf22. Fgf22 null animals were viable, fertile and did not display any obvious abnormalities. No differences in skin histology and pelage hair were observed, demonstrating that FGF22 is dispensable during embryogenesis and in unchallenged adult skin. Mice lacking FGF22 were able to heal acute wounds just as efficiently as wild type mice. However, classical two-step skin carcinogenesis challenge revealed that Fgf22 null mice developed considerably less papillomas than wild type mice. Interestingly, Fgf22 knockout mice displayed a significant reduction in body weight and I identified several novel sites of Fgf22 expression in the gastrointestinal tract. However, the morphology and function of various tested tissues of the digestive system were not affected by Fgf22 deletion and the mechanism underlying metabolic differences between Fgf22 wild type and knockout mice remains unknown. FGF22 signals through FGFR2b, a receptor tyrosine kinase that we recently have shown plays a tumour-suppressive role in the mouse skin. Another aspect of my project was to verify whether FGFR2 plays a similar role in human skin, by investigating squamous cell carcinoma (SCC) sections and cell lines isolated from patient SCCs. I observed differences in the pattern of anti-FGFR2 4 immunostaining of normal skin and tumours. Also, since it is well documented that mutations in FGFR2 arise in patients with different types of cancer, I screened DNA isolated from the cell lines and identified eleven different mutations in FGFR2. This study contributes towards a better understanding of the wide spectrum of FGF/FGFR activities and distinct regulatory functions in the biology of physiological and pathological processes.