Mesenchymal Stromal Cells Promote Tumor Growth through the Enhancement of Neovascularization
Mesenchymal Stromal Cells Promote Tumor Growth through the Enhancement of Neovascularization
复制标题
DOI：
10.2119/molmed.2010.00157
复制
发表时间：
2011-07-01
影响因子：
5.7
通讯作者：
Saijo, Yasuo
中科院分区：
文献类型：
--
作者：
Suzuki, Kazuhiro;Sun, Ruowen;Saijo, Yasuo
间充质基质细胞（MSC），也称为间充质干细胞，在肿瘤组织中迁移并发挥基质细胞的作用。间充质干细胞对肿瘤生长的影响存在争议。在这项研究中，我们发现间充质干细胞在体外可以增加肿瘤细胞的增殖，并在体内促进肿瘤的生长。我们还进一步分析了这些影响的机制。为了用于体外和体内实验，我们从 C57BL/6 小鼠中分离的细胞建立了骨髓来源的间充质基质细胞系。在与 B16-LacZ 细胞共培养模型中分析了小鼠 MSC 对体外肿瘤细胞增殖的影响。与 MSC 共培养和用 MSC 条件培养基处理均导致 B16-LacZ 细胞生长增强，尽管共培养细胞中生长刺激的幅度大于用条件培养基处理的细胞。与单独注射 B16-LacZ 细胞相比，将 B16-LacZ 细胞和 MSC 共同注射到同基因小鼠中会导致肿瘤尺寸增加。使用 Lewis 肺癌 (LLC) 细胞代替 B16-LacZ 细胞进行的相同实验产生了相似的结果。与新血管形成在 MSC 介导的肿瘤生长中的作用一致，在由 B16-LacZ 细胞或 LLC 与 MSC 共注射引起的肿瘤中，肿瘤血管面积比单独注射癌细胞诱导的肿瘤更大，共注射的 MSC 通过靠近血管壁定位并表达内皮标记物来直接支持肿瘤脉管系统。此外，与单独的B16-LacZ细胞相比，MSC和B16-LacZ细胞共培养时白血病抑制因子、巨噬细胞集落刺激因子、巨噬细胞炎症蛋白2和血管内皮生长因子的分泌增加。总之，这些结果表明间充质干细胞在体外和体内促进肿瘤生长，并表明体内肿瘤的促进可能部分归因于增强的血管生成。 (C) 2011 年范斯坦医学研究所，www.feinsteininstitute.org
Mesenchymal stromal cells (MSCs), also called mesenchymal stem cells, migrate and function as stromal cells in tumor tissues. The effects of MSCs on tumor growth are controversial. In this study, we showed that MSCs increase proliferation of tumor cells in vitro and promote tumor growth in vivo. We also further analyzed the mechanisms that underlie these effects. For use in in vitro and in vivo experiments, we established a bone marrow-derived mesenchymal stromal cell line from cells isolated in C57BL/6 mice. Effects of murine MSCs on tumor cell proliferation in vitro were analyzed in a coculture model with B16-LacZ cells. Both coculture with MSCs and treatment with MSC-conditioned media led to enhanced growth of B16-LacZ cells, although the magnitude of growth stimulation in cocultured cells was greater than that of cells treated with conditioned media. Co-injection of B16-LacZ cells and MSCs into syngeneic mice led to increased tumor size compared with injection of B16-LacZ cells alone. Identical experiments using Lewis lung carcinoma (LLC) cells instead of B16-LacZ cells yielded similar results. Consistent with a role for neovascularization in MSC-mediated tumor growth, tumor vessel area was greater in tumors resulting from co-injection of B16-LacZ cells or LLCs with MSCs than in tumors induced by injection of cancer cells alone, Co-injected MSCs directly supported the tumor vasculature by localizing close to vascular walls and by expressing an endothelial marker. Furthermore, secretion of leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2 and vascular endothelial growth factor was increased in cocultures of MSCs and B16-LacZ cells compared with B16-LacZ cells alone. Together, these results indicate that MSCs promote tumor growth both in vitro and in vivo and suggest that tumor promotion in vivo may be attributable in part to enhanced angiogenesis. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org