title: Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.
abstract: Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Shih-Ya
authors.initials: SY
authors.lastname: Hung
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan; Department of Materials Science and Engineering, Feng Chia University, Taichung, Taiwan.
authors.forename: Hsien-Te
authors.initials: HT
authors.lastname: Chen
authors.affiliation: Department of Materials Science and Engineering, Feng Chia University, Taichung, Taiwan; Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Early Childhood Care and Education, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan.
authors.forename: Hsi-Kai
authors.initials: HK
authors.lastname: Tsou
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. Electronic address: chtang@mail.cmu.edu.tw.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000098:blood supply / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D020813:Receptor, trkB / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D042461:Vascular Endothelial Growth Factor A; D020813:Receptor, trkB
keywords: Angiogenesis; BDNF; Chondrosarcoma; TrkB; VEGF