Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma
Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma
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DOI：
10.1158/1078-0432.ccr-10-2381
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发表时间：
2011-04-01
影响因子：
11.5
通讯作者：
Vacca, Angelo
中科院分区：
文献类型：
--
作者：
De Luisi, Annunziata;Ferrucci, Arianna;Vacca, Angelo
目的：为了确定来那度胺（IMiD免疫调节药物的“先导化合物”）在活动期多发性骨髓瘤（MM）患者骨髓（BM）内皮细胞（EC）中的体内和体外抗血管生成能力。体外功能研究（血管生成、“伤口”愈合和趋化性、细胞活力、粘附和凋亡）在原代MMEC和意义不明的单克隆丙种球蛋白病（MGUS）患者（MGEC）或健康人脐静脉内皮细胞（HUVEC）的EC中进行。实时逆转录酶PCR，蛋白质印迹和差异蛋白质组学分析，用于相关的形态学和生物EC功能与来那度胺的影响，在基因和蛋白质level.Results：来那度胺产生了相关的抗血管生成作用在体内在1.75 μ mol/L，剂量达到25 mg/d治疗的患者间质液。在体外，来那度胺抑制MMECs的血管生成和迁移，但不抑制MGECs或对照HUVECs，并且对MMEC活力、凋亡或纤连蛋白和玻连蛋白介导的粘附没有影响。来那度胺处理的MMECs显示VEGF/VEGFR 2信号通路和几种控制EC运动、细胞骨架重塑和能量代谢通路的蛋白质的变化。结论：本研究提供了来那度胺在原发性MMECs中的抗迁移和抗血管生成作用相关的分子机制的信息，从而为MM的有效内皮靶向治疗提供了新的途径。1935-46.（C）2011年《非洲标准化评论》。
Purpose: To determine the in vivo and in vitro antiangiogenic power of lenalidomide, a "lead compound" of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC).Experimental Design: The antiangiogenic effect in vivo was studied using the chorioallantoic membrane (CAM) assay. Functional studies in vitro (angiogenesis, "wound" healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels.Results: Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 mu mol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. In vitro, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin-and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways.Conclusions: This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies in MM. Clin Cancer Res; 17(7); 1935-46. (C)2011 AACR.