Belloni Daniela, Marcatti Magda, Ponzoni Maurilio, Ciceri Fabio, Veschini Lorenzo, Corti Angelo, Caligaris Cappio Federico, Ferrarini Marina, Ferrero Elisabetta
Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.
Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
Exp Cell Res. 2015 Jan 1;330(1):1-12. doi: 10.1016/j.yexcr.2014.10.017. Epub 2014 Oct 24.
Angiopoietin-2 (Ang-2) is involved in angiogenesis in both solid and hematological malignancies. In Multiple Myeloma (MM), serum Ang-2 correlates with disease progression and response to therapy. To address the patho-physiologic role of Ang-2 in MM associated angiogenesis, we used sera from patients with active MM, which contained significantly higher levels of the molecule, compared to those from patients with smoldering MM and Monoclonal Gammopathy of Undetermined Significance. MM Bone Marrow (BM) sera with high Ang-2 concentration specifically contributed to endothelial cell (EC) activation, while Ang-1 containing sera maintained EC stabilization. The functional dichotomy of Ang-1 and Ang-2 was confirmed by the triggering of distinctive signaling pathways down-stream the common Tie-2 receptor, i.e., the Akt or the ERK- phosphorylation pathway. Notably, Ang-2 but not VEGF serum levels correlated with BM micro-vessel density, further underscoring the key role of Ang-2 in angiogenesis. Western Blot, RT-PCR and immunocytochemistry identified MMEC as the major source of Ang-2, at variance with MM cells and CD14(+) BM monocytes. These data suggest that Ang-2 produced in the BM milieu may contribute to MM angiogenesis and suggest that the molecule can be further exploited both as angiogenesis biomarker and as a potential therapeutic target.
血管生成素-2（Ang-2）参与实体瘤和血液系统恶性肿瘤的血管生成。在多发性骨髓瘤（MM）中，血清Ang-2与疾病进展及治疗反应相关。为探讨Ang-2在MM相关血管生成中的病理生理作用，我们使用了活动性MM患者的血清，与冒烟型MM患者及意义未明的单克隆丙种球蛋白病患者的血清相比，前者所含该分子水平显著更高。高Ang-2浓度的MM骨髓（BM）血清特异性地促成内皮细胞（EC）活化，而含Ang-1的血清维持EC稳定。通过共同的Tie-2受体下游独特信号通路（即Akt或ERK磷酸化通路）的激活，证实了Ang-1和Ang-2的功能二分法。值得注意的是，Ang-2而非VEGF血清水平与BM微血管密度相关，进一步强调了Ang-2在血管生成中的关键作用。蛋白质免疫印迹法、逆转录-聚合酶链反应（RT-PCR）及免疫细胞化学鉴定出MMEC是Ang-2的主要来源，这与MM细胞及CD14(+) BM单核细胞不同。这些数据表明，BM微环境中产生的Ang-2可能促成MM血管生成，并提示该分子可进一步用作血管生成生物标志物及潜在治疗靶点。
