Hose Dirk, Moreaux Jérôme, Meissner Tobias, Seckinger Anja, Goldschmidt Hartmut, Benner Axel, Mahtouk Karène, Hillengass Jens, Rème Thierry, De Vos John, Hundemer Michael, Condomines Maud, Bertsch Uta, Rossi Jean-François, Jauch Anna, Klein Bernard, Möhler Thomas
Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Blood. 2009 Jul 2;114(1):128-43. doi: 10.1182/blood-2008-10-184226. Epub 2009 Mar 18.
Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
几乎所有需要治疗的骨髓瘤患者都存在丰富的骨髓血管生成，且与治疗反应和生存率相关。我们通过Affymetrix DNA微阵列评估了466个样本中402个血管生成相关基因的表达，这些样本包括来自300例未经治疗患者的CD138纯化骨髓瘤细胞（MMCs），通过动态对比增强磁共振成像评估体内微循环，并进行体外血管生成（血管生成试剂盒检测）。正常骨髓浆细胞（BMPCs）表达的促血管生成基因（如VEGFA、ADM、IGF-1）中位数为39个，抗血管生成基因（如TIMP1、TIMP2）中位数为28个。与记忆B细胞不同，BMPCs的上清液在体外可诱导血管生成。MMCs表达的促血管生成基因（45个）或抗血管生成基因（31个）中位数没有显著更高，但97%的MMC样本异常表达血管生成因子HGF、IL-15、ANG、APRIL、CTGF或TGFA中的至少一种。与BMPCs相比，MMCs和人骨髓瘤细胞系的上清液在体外诱导的血管生成显著更高。总之，BMPCs表达的促血管生成基因多于抗血管生成基因，这赋予了其在体外诱导血管生成的能力。MMCs促血管生成基因的异常表达和抗血管生成基因的下调进一步增加了血管生成刺激，共同导致所有骨髓瘤患者不同程度的骨髓血管生成。
