The proangiogenic role of brain-derived neurotrophic factor in tumor development

Abstract

Background and Aim: Hepatocellular carcinoma is a hypervascularized solid tumor which requires angiogenesis for its growth. Previous studies suggested that neurotrophins, such as brain-derived neurotrophic factor (BDNF), may serve as angiogenic factors. The involvement of BDNF in tumor angiogenesis, however, remains unclear. The present study aimed at elucidating the role of BDNF in regulating angiogenesis and tumor development. Materials and Methods: BDNF was overexpressed in a normal mouse endothelial cell line by transfection. The angiogenic properties, including proliferation, cell motility, invasiveness and cell survival, of the transfectants were subsequently assessed by MTT, cell migration, invasion and Annexin V labeling assays, respectively. Microarray analysis was performed to explore the BDNF-mediated angiogenic pathway. An in vivo cell co-injection model, using a mouse transformed hepatocyte cell line and BDNF transfectants, was used to study the role of BDNF in tumor development. Results: Firstly, overexpression of BDNF could promote endothelial cell proliferation, migration, invasion and survival. Secondly, the gene expression profiling data suggested that the BDNF-induced angiogenic effects could be attributed to a dozen of genes including transcription factors, cell adhesion molecules, chemokines and growth factors. Thirdly, the in vivo cell co-injection experiment showed that high BDNF-expressing endothelial cells are able to promote growth of tumors with significantly higher number of microvessels. On the other hand, knock-down of BDNF in a tumor-derived endothelial cell line by shRNAs impairs such tumor promoting effect. Conclusion: The present study showed that BDNF is crucial for tumor angiogenesis and may serve as a potential target for anti-angiogenic treatment.