title: Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: implication in hepatocellular carcinoma.
abstract: OBJECTIVE
  Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development.
  
  
  METHODS
  BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance.
  
  
  RESULTS
  Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival.
  
  
  CONCLUSIONS
  BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC.
authors.affiliation: Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Chi-Tat
authors.initials: CT
authors.lastname: Lam
authors.forename: Zhen-Fan
authors.initials: ZF
authors.lastname: Yang
authors.forename: Chi-Keung
authors.initials: CK
authors.lastname: Lau
authors.forename: Ka-Ho
authors.initials: KH
authors.lastname: Tam
authors.forename: Sheung-Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D034741:RNA, Small Interfering