Abstract: Background　Multiple myeloma（MM） is a plasma cell tumor with hypercalcemia，renal insufficiency，anemia，and bone lesions that often occurs in middle-aged and elderly people.There is a trend showing a notably increased incidence of MM recently.However，the pathogenesis of MM is unknown，which may be related to the complex and abnormal tumor microenvironment.Objective　To estimate the correlation of vascular cell adhesion molecule-1（VCAM-1），activin A and other cytokines in tumor microenvironment with the pathogenesis of MM and related clinical significance in MM patients.Methods　Participants were selected from Beijing Chao-yang Hospital（West），Capital Medical University from January 2012 to April 2014，including 20 healthy physical examinees（healthy group） and 50 inpatients with MM from Department of Hematology and Oncology（MM group）.MM patients were classified into newly diagnosed（n=18），relapsed（n=18），and response（n=14） subgroups by post-treatment conditions，kidney impairment（n=12） and non-kidney impairment subgroups（n=38） by kidney impairment prevalence （serum creatinine>177 μmmol/L），anemia（n=29 and non-anemia subgroups（n=21） by anemia prevalence（Hb<100 g/L），and severe bone lesion（n=27） and non-severe bone lesion subgroups（n=23） by bone lesion level.ELISA was used to measure VCAM-1，activin A，bone metabolic markers〔25-（OH）D3，serum bone-specific alkaline phosphatase，tartrate-resistant acid phosphatase，serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen，IL-6，IL-6R，TNF-α and VEGF〕in MM patients were detected and compared by ELISA.Pearson correlation analysis was conducted.The best cutoff values of VCAM-1 and activin A were evaluated by receiver operating characteristic curve （ROC），draw survival curve.Results　The healthy controls had lower mean levels VCAM-1 and activin A than newly diagnosed and relapsed MM patients（P<0.05）.Response MM patients had lower mean levels VCAM-1 and activin A than newly diagnosed and relapsed MM patients（P<0.05）.The kidney impairment MM patients had higher mean levels of VCAM-1 and activin A than healthy controls（P<0.05），so did non-kidney impairment MM patients （P<0.05）.The kidney impairment MM patients showed higher mean levels of VCAM-1 and activin A compared to non-kidney impairment MM patients（P<0.05）.Anemia MM patients had higher mean levels of VCAM-1 and activin A than non-anemia MM patients（P<0.05）.Both MM patients with and without severe bone lesions had higher mean level of activin A than healthy controls（P<0.05）.The mean level of activin A in MM patients with severe bone lesions was significantly higher than those without （P<0.05）.VCAM-1 was positively correlated with activin A（r=0.627，P<0.001），serum creatinine（r=0.415，P=0.004），β2-microglobulin（r=54.97，P=0.001），lactate dehydrogenase（r=0.968，P=0.028），and the number of myeloma cells in the bone marrow microenvironment（r=1 684.38，P=0.045），but was negatively correlated with albumin（r=-0.589，P<0.001） and Hb（r=-0.589，P<0.001）.ROC curve analysis found that in predicting MM，the optimal diagnostic threshold of VCAM-1 was 1 443.3 μg/L，and that of activin A was 550.7 ng/L.Survival analysis found that MM patients with VCAM-1>1 443.3μg/L had significantly lower cumulative survival rate（χ2=17.105，P<0.001）.And MM patients with activin A> 550.7 ng/L had significantly lower cumulative survival rate（χ2=15.379，P<0.001）.Conclusion　Both elevated VCAM-1 and activin A in the tumor microenvironment are related to the pathological process of nephropathy，anemia and bone disease，and together participate in the progression of MM，suggesting that they may become a new target for anti-MM therapy in the future.

Key words: Multiple myeloma, Vascular cell adhesion molecule-1, Activin A, Kidney injured , Anemia, Bone lesions

摘要： 背景　多发性骨髓瘤（MM）是一好发于中老年人的伴有高钙血症、肾损害、贫血及骨质破坏的浆细胞肿瘤，近几年MM发病率明显增高。MM发病机制不明，可能与MM患者复杂的异常肿瘤微环境有关。目的　探究MM患者肿瘤微环境中血管细胞黏附分子-1（VCAM-1）和激活素A对MM发病的影响。方法　选取2012年1月—2014年4月北京朝阳医院西院血液与肿瘤科收治的50例MM住院患者作为研究对象，同时选取在本院体检的健康人20例作为对照组。根据治疗后患者的病情状态分组，新诊断MM（NDMM）组18例、复发MM（RMM）组18例和治疗反应（RG）组14例。根据是否有肾损害〔血肌酐（Scr）>177 μmmol/L〕分为肾损害组（KI）组12例及非肾损害（NKI）组38例；根据是否有贫血〔血红蛋白（Hb）<100 g/L〕分为贫血组29例及非贫血组21例；根据患者骨病程度分为严重骨病变（SBL）组27例和非严重骨病变（NSBL）组23例。应用ELISA法检测MM患者VCAM-1、激活素A、骨代谢标志物〔25-羟维生素D3、血清骨特异性碱性磷酸酶（bALP）、抗酒石酸酸性磷酸酶（TRACP-5b）和Ⅰ型胶原吡啶交联终肽（ICTP）、白介素（IL）-6、IL-6R、肿瘤坏死因子α（TNF-α）和血管内皮生长因子（VEGF）〕水平。相关性分析采用Pearson相关分析。采用受试者工作特征曲线（ROC曲线）评价VCAM-1和激活素A诊断MM的最佳截断值，绘制生存曲线。结果　NDMM组、RMM组VCAM-1、激活素A水平均高于对照组（P<0.05）；NDMM组、RMM组VCAM-1、激活素A水平高于RG组（P<0.05）；NDMM组激活素A水平高于RG组（P<0.05）。KI组VCAM-1、激活素A水平高于NKI组、对照组（P<0.05）。NKI组VCAM-1、激活素A水平高于对照组（P<0.05）。贫血组VCAM-1、激活素A水平高于非贫血组（P<0.05）。SBL组、NSBL组激活素A水平高于对照组（P<0.05）；SBL组激活素A水平高于NSBL组（P<0.05）。VCAM-1水平与激活素A（r=0.627，P<0.001）、Scr（r=0.415，P=0.004）、β2-微球蛋白（r=54.97，P=0.001）、乳酸脱氢酶（r=0.968，P=0.028）、骨髓中骨髓瘤细胞数目（r=1 684.38，P=0.045）呈正相关；与清蛋白（r=-0.589，P<0.001）和Hb水平（r=-0.589，P<0.001）呈负相关。根据ROC曲线得出VCAM-1诊断MM的最佳截断值为1 443.3 μg/L、激活素A诊断MM的最佳截断值为550.7 ng/L。VCAM-1>1 443.3 μg/L患者累积生存率低于VCAM-1<1 443.3 μg/L（χ2=17.105，P<0.001）。激活素A>550.7 ng/L患者累积生存率低于<550.7 ng/L（χ2=15.379，P<0.001）。结论　肿瘤微环境中升高的VCAM-1和激活素A一起参与MM病情进展，且与肾病、贫血和骨病病理过程有关，提示其有希望成为未来抗MM治疗的新靶点。

关键词: 多发性骨髓瘤, 血管细胞黏附分子1, 激活素A, 肾损害, 贫血, 骨损害