Fibroblast Growth Factor 9 is expressed by activated hepatic stellate cells and promotes progression of hepatocellular carcinoma

Tatjana Seitz,Kim Freese,Wolfgang Erwin Thasler,Claus Hellerbrand,Peter Dietrich,Anja Bosserhoff

doi:10.1038/s41598-020-61510-4

Abstract

Hepatocellular carcinoma (HCC) is closely associated with liver fibrosis. Hepatic stellate cells (HSC) and cancer-associated myofibroblasts are key players in liver fibrogenesis and hepatocarcinogenesis. Overexpression of fibroblast growth factor (FGF) receptors contributes to HCC development and progression. This study aimed to elucidate the role of FGFs in the HSC-HCC crosstalk. Analysis of the expression of the fifteen paracrine FGF-members revealed that FGF9 was only expressed by HSC but not by HCC cells. Also in human HCC tissues, HSC/stromal myofibroblasts were identified as cellular source of FGF9. High expression levels of FGF9 significantly correlated with poor patient survival. Stimulation with recombinant FGF9 induced ERK- and JNK-activation combined with significantly enhanced proliferation, clonogenicity, and migration of HCC cells. Moreover, FGF9 significantly reduced the sensitivity of HCC cells against sorafenib. Protumorigenic effects of FGF9 on HCC cells were almost completely abrogated by the FGFR1/2/3 inhibitor BGJ398, while the selective FGFR4 inhibitor BLU9931 had no significant effect. In conclusion, these data indicate that stroma-derived FGF9 promotes tumorigenicity and sorafenib resistance of HCC cells and FGF9 overexpression correlates with poor prognosis in HCC patients. Herewith, FGF9 appears as potential prognostic marker and novel therapeutic target in HCC.

Highlights

Hepatocellular carcinoma (HCC) is closely associated with liver fibrosis
Overexpression of FGFR2 and FGFR3 contributes to HCC development and metastasis[9,10], further suggesting that fibroblast growth factor (FGF)-signaling plays an important role in HCC
While most previous studies had focused on the role of FGF receptors (FGFR) in HCC, the aim of the present study was to get a deeper understanding of the expression and tumorigenic effects of different FGFR-ligands with a focus on paracrine FGFs and their role in the hepatic stellate cells (HSC)-HCC crosstalk

Summary

Introduction

Hepatocellular carcinoma (HCC) is closely associated with liver fibrosis. Hepatic stellate cells (HSC) and cancer-associated myofibroblasts are key players in liver fibrogenesis and hepatocarcinogenesis. Protumorigenic effects of FGF9 on HCC cells were almost completely abrogated by the FGFR1/2/3 inhibitor BGJ398, while the selective FGFR4 inhibitor BLU9931 had no significant effect These data indicate that stroma-derived FGF9 promotes tumorigenicity and sorafenib resistance of HCC cells and FGF9 overexpression correlates with poor prognosis in HCC patients. A better understanding of the role of HSC and their crosstalk with HCC cells may provide new therapeutic options for the treatment of HCC. Fibroblast growth factor (FGF) signaling plays an important role in the regulation of many biological processes such as development, cell proliferation and differentiation, and its dysregulation is reported in different types of diseases including cancers[6]. Overexpression of FGFR2 and FGFR3 contributes to HCC development and metastasis[9,10], further suggesting that FGF-signaling plays an important role in HCC

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