Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells
Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells
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DOI：
10.3324/haematol.2013.090977
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发表时间：
2014-01-01
期刊：
影响因子：
10.1
通讯作者：
Zannettino, Andrew C. W.
中科院分区：
文献类型：
--
作者：
Noll, Jacqueline E.;Williams, Sharon A.;Zannettino, Andrew C. W.
多发性骨髓瘤是一种无法治愈的血液学癌症，其特征是骨髓内恶性浆细胞的克隆性增殖。大量研究表明，骨髓瘤浆细胞占据并改变骨髓基质组织，是增强骨髓瘤存活和生长的一种手段。然而，基质细胞组织变化的性质和程度仍有待确定。在本研究中，我们利用骨髓间充质基质细胞和成骨细胞相关细胞表面标志物（分别为STRO-1和碱性磷酸酶）的表达和流式细胞术计数诊断时骨髓瘤患者骨髓间充质基质细胞和成骨细胞的数量。使用这种方法，我们发现STRO-1阳性集落形成间充质间质细胞数量增加，碱性磷酸酶成骨细胞数量减少。值得注意的是，这种间充质间质细胞数量的增加与诊断时的浆细胞负荷密切相关。此外，与成骨细胞群体相比，STRO-1+间充质基质细胞群体表达更高水平的浆细胞和破骨细胞激活因子，包括RANKL和IL-6，这提供了间充质基质细胞增加可能促进和帮助骨髓瘤进展的机制。重要的是，这些发现在骨髓瘤的C57BL/KaLwRij小鼠模型中得到了真实的复制，这表明该模型可能提供了一种独特的临床相关系统，可以识别和治疗性地调节骨微环境，进而改变骨髓瘤疾病的进展。
Multiple myeloma is an incurable hematologic cancer characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Numerous studies suggest that the myeloma plasma cells occupy and alter the stromal tissue of the bone marrow as a means of enhancing their survival and growth. However, the nature and magnitude of the changes to the stromal cell tissue remain to be determined. In this study, we used mesenchymal stromal cell and osteoblast-related cell surface marker expression (STRO-1 and alkaline phosphatase, respectively) and flow cytometry to enumerate mesenchymal stromal cell and osteoblast numbers in bone marrow recovered from myeloma patients at the time of diagnosis. Using this approach, we identified an increase in the number of STRO-1 positive colony forming mesenchymal stromal cells and a concomitant decrease in alkaline phophatase osteoblasts. Notably, this increase in mesenchymal stromal cell numbers correlated closely with plasma cell burden at the time of diagnosis. In addition, in comparison with the osteoblast population, the STRO-1+ mesenchymal stromal cell population was found to express higher levels of plasma cell-and osteoclast-activating factors, including RANKL and IL-6, providing a mechanism by which an increase in mesenchymal stromal cells may promote and aid the progression of myeloma. Importantly, these findings were faithfully replicated in the C57BL/KaLwRij murine model of myeloma, suggesting that this model may present a unique and clinically relevant system in which to identify and therapeutically modulate the bone microenvironment and, in turn, alter the progression of myeloma disease.