Neovascular niche for human myeloma cells in immunodeficient mouse bone.
Neovascular niche for human myeloma cells in immunodeficient mouse bone.
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DOI：
10.1371/journal.pone.0030557
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Suda T
中科院分区：
文献类型：
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作者：
Iriuchishima H;Takubo K;Miyakawa Y;Nakamura-Ishizu A;Miyauchi Y;Fujita N;Miyamoto K;Miyamoto T;Ikeda E;Kizaki M;Nojima Y;Suda T
与骨髓（BM）的相互作用在多发性骨髓瘤（MM）的病理生理学特征中起着至关重要的作用，包括细胞增殖、化疗耐药性和骨病变进展。为了表征MM-BM相互作用，我们利用了人MM的体内实验模型，其中将表达GFP的人MM细胞系移植到NOG小鼠中（NOG-hMM模型）。移植的MM细胞优先在BM骨内膜的干骺端区域植入，并与成骨细胞和破骨细胞形成复合物。MM细胞亚群在移植后表达VE-钙粘蛋白，并在BM中形成内皮样结构。在NOG-hMM模型中，向小鼠施用氮芥衍生物苯达莫司汀后，BM中的CD 138+骨髓瘤细胞通过p53依赖性凋亡减少。苯达莫司汀维持骨表面的成骨细胞衬里并保护细胞外基质结构。此外，苯达莫司汀抑制NOG-hMM模型中破骨细胞和间充质细胞的生长。由于VE-钙粘蛋白+ MM细胞与VE-钙粘蛋白-群体相比具有化学抗性、缺氧和HIF-2α阳性，因此VE-钙粘蛋白诱导可能取决于氧合状态。这里描述的NOG-hMM模型是一个有用的系统，用于分析MM病理生理学的动力学，MM细胞与其他细胞区室的相互作用，以及新型抗MM疗法的效用。
The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138+ myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin+ MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin− population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.