Brain-Derived Neurotrophic Factor Promotes Tumorigenesis via Induction of Neovascularization: Implication in Hepatocellular Carcinoma

• Published in: Clinical cancer research Vol. 17; no. 10; pp. 3123 - 3133
• Main Authors: LAM, Chi-Tat, YANG, Zhen-Fan, LAU, Chi-Keung, TAM, Ka-Ho, FAN, Sheung-Tat, POON, Ronnie T. P
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2011
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Brain-Derived Neurotrophic Factor - antagonists & inhibitors; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - physiology; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cells, Cultured; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - drug effects; Humans; Liver Neoplasms - blood supply; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Pharmacology. Drug treatments; RNA, Small Interfering - pharmacology; Tumors; Up-Regulation - drug effects; Up-Regulation - genetics; Xenograft Model Antitumor Assays; Liver cancer; Induction; Digestive diseases; Hepatic disease; Hepatocellular carcinoma; Tumorigenicity; Malignant tumor; Brain derived neurotrophic factor; Neovascularization; Carcinogenesis; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-2802

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. 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. 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. BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC.