The fibroblast growth factor (FGF) family comprises 22 proteins. FGFs can be divided
into seven subfamilies and are classified into paracrine, intracrine and endocrine
factors. FGFs play a major role in embryonic development, differentiation and wound
healing. Liver fibrosis can be considered as chronic wound healing response, and hepatocellular
carcinoma (HCC) frequently develops in this wound "that never heals". The activation
of hepatic stellate cells (HSC) is a key event of hepatic fibrosis and activated HSC
are known to promote HCC progression, however, the role of different FGFs in HCC is
largely unknown.
The aim of this study was to identify FGFs that are expressed by HSC and affect HCC
progression.
Methods and Results:
First, we screened for FGFs that increased during in vitro activation of human HSC
and in different murine models of hepatic fibrosis; a further criterion was significant
correlation with markers of activated HSC (collagen I and alpha-smooth muscle actin
expression) in liver tissues of patients with different types of chronic liver disease.
FGF-1/2, FGF-5, FGF-7/10 and FGF-9 fulfilled these criteria. In subsequent analysis,
we focused on FGF-9, and found that its expression was almost undetectable in different
human HCC cell lines (Hep3B, HepG2, Huh7, PLC) compared with activated HSCs. Fitting
to this, FGF9 expression correlated significantly with collagen expression in human
HCC tissues. Importantly, TCGA (The Cancer Genome Atlas) data set analysis of 381
HCC patients revealed that high FGF9 expression in HCC correlated with poor patient
survival. In functional in vitro analysis, recombinant FGF9 (rFGF9) induced proliferation,
colony formation and migratory activity of human HCC cell lines. Furthermore, rFGF9
inhibited etoposide-induced apoptosis of HCC cells. Moreover, rFGF9 significantly
decreased the efficacy of sorafenib to inhibit proliferation and to induce cell death
in HCC cells.
Summary and conclusion:
FGF9 derived from activated HSC enhances the tumorigenicity and therapy resistance
of HCC cells embedded in a fibrotic microenvironment. Herewith, FGF9 appears as potential
prognostic parameter and promising therapeutic target in HCC.
