title: Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis.
abstract: Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several non-liver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells.
  
  
  CONCLUSIONS
  FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy.
authors.affiliation: Institute of Cancer Research, Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Gauglhofer
authors.forename: Sandra
authors.initials: S
authors.lastname: Sagmeister
authors.forename: Waltraud
authors.initials: W
authors.lastname: Schrottmaier
authors.forename: Carina
authors.initials: C
authors.lastname: Fischer
authors.forename: Chantal
authors.initials: C
authors.lastname: Rodgarkia-Dara
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.forename: Stefan
authors.initials: S
authors.lastname: Stättner
authors.forename: Christoph
authors.initials: C
authors.lastname: Bichler
authors.forename: Daniela
authors.initials: D
authors.lastname: Kandioler
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Rolf
authors.initials: R
authors.lastname: Schulte-Hermann
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D008113:Liver Neoplasms / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis*; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: C484724:FGF17 protein, human; C496456:FGF8 protein, human; D017468:Receptors, Fibroblast Growth Factor; C113569:fibroblast growth factor 18; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases