Hu Yu, Wang Ya-dan, Guo Tao, Wei Wen-ning, Sun Chun-yan, Zhang Lu, Huang Jin
Institute of Hematology, Union Hospital, Tongji Medical College, Huanzhong University of Science and Technology, 1277 Jiefang Dadao, Wuhan 430022, P.R. China.
Cancer Genet Cytogenet. 2007 Oct 1;178(1):1-10. doi: 10.1016/j.cancergencyto.2007.05.028.
Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, but the angiogenic properties of myeloma cells and the mechanism of MM-induced angiogenesis have not been completely clarified. The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB, have been identified as critical factors in the regulation of vessel formation. In this study, we demonstrate that patients with MM had increased BDNF and vascular endothelial growth factor (VEGF) in their peripheral blood. We also found in particular that a decreased BDNF level was correlated with the remission of MM. BDNF was expressed by the human myeloma cell line RPMI8226 and primary myeloma cells, and TrkB was expressed by human umbilical vein endothelial cells (HUVEC) at the protein levels. In a coculture system, we observed that both RPMI8226 cells and primary myeloma cells induced the migration and formation of a net-like structure in HUVEC. The anti-BDNF monoclonal antibody significantly but partially restrained the angiogenesis effect of MM cells. Moreover, in an experimental model of angiogenesis in vivo, BDNF and VEGF significantly promoted vessel formation in Matrigel plug compared to the control. These effects were also blocked by anti-BDNF monoclonal antibody. Finally, our in vitro results were supported by the in vivo finding in human myeloma xenograft NOD/SCID models. Anti-BDNF mAb treatment resulted in inhibition of tumor growth, decreased vessel density, and tumor necrosis. Our study suggested that the BDNF/TrkB signaling pathway could be involved, at least in part, in MM-induced angiogenesis.
多发性骨髓瘤（MM）患者的骨髓血管生成增加，但骨髓瘤细胞的血管生成特性以及MM诱导血管生成的机制尚未完全阐明。脑源性神经营养因子（BDNF）及其高亲和力受体TrkB已被确定为血管形成调节中的关键因子。在本研究中，我们证明MM患者外周血中的BDNF和血管内皮生长因子（VEGF）增加。我们还特别发现BDNF水平降低与MM缓解相关。人骨髓瘤细胞系RPMI8226和原代骨髓瘤细胞表达BDNF，人脐静脉内皮细胞（HUVEC）在蛋白水平表达TrkB。在共培养系统中，我们观察到RPMI8226细胞和原代骨髓瘤细胞均诱导HUVEC迁移并形成网状结构。抗BDNF单克隆抗体显著但部分抑制了骨髓瘤细胞的血管生成作用。此外，在体内血管生成实验模型中，与对照组相比，BDNF和VEGF显著促进基质胶栓中的血管形成。这些作用也被抗BDNF单克隆抗体阻断。最后，我们的体外结果得到了人骨髓瘤异种移植NOD/SCID模型体内研究结果的支持。抗BDNF单克隆抗体治疗导致肿瘤生长受抑制、血管密度降低和肿瘤坏死。我们的研究表明，BDNF/TrkB信号通路可能至少部分参与MM诱导的血管生成。
