Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
Oncogene. 2012 May 3;31(18):2258-69. doi: 10.1038/onc.2011.412. Epub 2011 Oct 3.
Bone marrow (BM) angiogenesis has an important role in the initiation and progression of multiple myeloma (MM). We looked at novel mechanisms of vessel formation in patients with MM through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with active MM (MMECs) and ECs of patients with monoclonal gammopathy of undetermined significance (MGECs) and of subjects with benign anemia (normal ECs). Four proteins were found overexpressed in MMECs: filamin A, vimentin, α-crystallin B and 14-3-3ζ/δ protein, not yet linked to overangiogenic phenotype. These proteins gave a typical distribution in the BM of MM patients and in MMECs versus MGECs, plausibly according to a different functional state. Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis. Their silencing RNA knockdown affected critical MMEC angiogenesis-related functions, such as spreading, migration and tubular morphogenesis. A gradual stabilization of 14-3-3ζ/δ protein was observed, with transition from normal ECs to MGECs and MMECs that may be a critical step for the angiogenic switch in MMECs and maintenance of the cell overangiogenic phenotype. These proteins were substantially impacted by anti-MM drugs, such as bortezomib, lenalidomide and panobinostat. Results suggest that these four proteins could be new targets for the antiangiogenic management of MM patients.
骨髓（BM）血管生成在多发性骨髓瘤（MM）的发生和进展中起着重要作用。我们通过对活动期 MM 患者的 BM 内皮细胞（MMECs）与单克隆丙种球蛋白血症意义未明（MGECs）患者和良性贫血患者（正常 ECs）的内皮细胞进行比较蛋白质组学分析，研究了 MM 患者血管形成的新机制。发现 MMECs 中有 4 种蛋白过表达：细丝蛋白 A、波形蛋白、α-晶体蛋白 B 和 14-3-3ζ/δ 蛋白，它们与过度血管生成表型尚未相关联。这些蛋白在 MM 患者的 BM 中和 MMECs 与 MGECs 中呈现典型分布，可能根据不同的功能状态。它们的表达在血管内皮生长因子、成纤维细胞生长因子 2、肝细胞生长因子和 MM 浆细胞条件培养基的作用下增强，与 MMEC 血管生成增强一致。它们的沉默 RNA 敲低影响了关键的 MMEC 血管生成相关功能，如扩展、迁移和管状形态发生。观察到 14-3-3ζ/δ 蛋白逐渐稳定，从正常 ECs 到 MGECs 和 MMECs 的转变，这可能是 MMECs 血管生成开关的关键步骤，也是维持细胞过度血管生成表型的关键步骤。这些蛋白受到硼替佐米、来那度胺和帕比司他等抗 MM 药物的显著影响。结果表明，这四种蛋白可能成为 MM 患者抗血管生成治疗的新靶点。
