title: Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis.
abstract: BACKGROUND
  Advanced hepatocellular carcinoma (HCC) is a neoplastic disease with a very bad prognosis and increasing worldwide incidence. HCCs are resistant to conventional chemotherapy and the multikinase inhibitor sorafenib is the only agent that has shown some clinical efficacy. It is therefore important to identify key molecular mechanisms driving hepatocarcinogenesis for the development of more efficacious therapies. However, HCCs are heterogeneous tumors and different molecular subclasses have been characterized. This heterogeneity may underlie the poor performance of most of the targeted therapies so far tested in HCC patients. The fibroblast growth factor 15/19 (FGF15/19), FGF receptor 4 (FGFR4) and beta-Klotho (KLB) correceptor signaling system, a key regulator of bile acids (BA) synthesis and intermediary metabolism, is emerging as an important player in hepatocarcinogenesis. Key Messages: Aberrant signaling through the FGF15/19-FGFR4 pathway participates in the neoplastic behavior of HCC cells, promotes HCC development in mice and its overexpression has been characterized in a subset of HCC tumors from patients with poorer prognosis. Pharmacological interference with FGF15/19-FGFR4 signaling inhibits experimental hepatocarcinogenesis, and specific FGFR4 inhibitors are currently being tested in selected HCC patients with tumoral FGF19-FGFR4/KLB expression.
  
  
  CONCLUSIONS
  Interference with FGF19-FGFR4 signaling represents a novel strategy in HCC therapy. Selection of candidate patients based on tumoral FGF19-FGFR4/KLB levels as biomarkers may result in increased efficacy of FGFR4-targeted drugs. Nevertheless, attention should be paid to the potential on target toxic effects of FGFR4 inhibitors due to the key role of this signaling system in BA metabolism.
authors.affiliation: CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Alvarez-Sola
authors.forename: Iker
authors.initials: I
authors.lastname: Uriarte
authors.forename: M Ujue
authors.initials: MU
authors.lastname: Latasa
authors.forename: Raquel
authors.initials: R
authors.lastname: Urtasun
authors.forename: Marina
authors.initials: M
authors.lastname: Bárcena-Varela
authors.forename: Maria
authors.initials: M
authors.lastname: Elizalde
authors.forename: Maddalen
authors.initials: M
authors.lastname: Jiménez
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Rodriguez-Ortigosa
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernández-Barrena
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005346:Fibroblast Growth Factors