title: Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF-A expression in hepatocellular carcinoma.
abstract: BACKGROUND
  Dysregulation and activation of Hedgehog (Hh) signalling may contribute to tumorigenesis, angiogenesis, and metastatic seeding in several solid tumours.
  
  
  OBJECTIVE
  We investigated the impact of Hh inhibition on tumour growth and angiogenesis using in-vitro and in-vivo models of hepatocellular carcinoma (HCC).
  
  
  METHODS
  The effect of the Hh pathway inhibitor GDC-0449 on tumour growth was investigated using an orthotopic rat model. Effects on angiogenesis were determined by immunohistochemical staining of von Willebrand factor antigen and by assessing the mRNA expression of several angiogenic factors. In vitro, HCC cell lines were treated with GDC-0449 and evaluated for viability and expression of vascular endothelial growth factor (VEGF). Endothelial cells were evaluated for viability, migration, and tube formation.
  
  
  RESULTS
  In the orthotopic HCC model, GDC-0449 significantly decreased tumoral VEGF expression which was accompanied by a significant reduction of microvessel density and tumour growth. In HCC cells, GDC-0449 had no effect on cell growth but significantly reduced target gene regulation and VEGF expression while having no direct effect on endothelial cell viability, migration, and tube formation.
  
  
  CONCLUSIONS
  Hh inhibition with GDC-0449 downregulates tumoral VEGF production in vitro and reduces tumoral VEGF expression, angiogenesis, and tumour growth in an orthotopic HCC model.
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Pinter
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sieghart
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Schmid
authors.affiliation: KH der Barmherzigen Brüder Wien, Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dauser
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Prager
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Dienes
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: AKH and Medical University of Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
keywords: Angiogenesis; GDC-0449; VEGF; hedgehog; hepatocellular carcinoma