Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model
Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model
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DOI：
10.1007/s12307-010-0041-8
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发表时间：
2010-12-01
影响因子：
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通讯作者：
Andreeff, Michael
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文献类型：
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作者：
Ling, Xiaoyang;Marini, Frank;Andreeff, Michael
我们先前证明了间充质干细胞/基质细胞（MSC）被招募到肿瘤中，并且MSC产生的IFN-β抑制了异种移植模型中的肿瘤生长。由于免疫系统缺陷，鼠异种移植模型不能完全重现进展期间肿瘤和免疫细胞的相互作用。因此，我们研究了MSC迁移和植入原发性乳腺肿瘤部位的能力，并随后在同基因免疫活性小鼠模型中探索MSC递送的IFN-β抑制肿瘤的机制。在此，我们报道了1）全身施用的MSC迁移到已建立的4个T1乳腺癌部位，并定位在肿瘤-基质边界和整个肿瘤块中; 2）由MSC分泌的高水平IFN-β在肿瘤微环境中可检测到，但在循环中不可检测到; 3）肿瘤内产生的IFN-β使信号转导激活物转录因子3（Stat 3），Src的组成性磷酸化失活，和Akt并下调cMyc和MMP 2在4个T1细胞中的表达，和4）在具有已建立的乳腺癌的小鼠中，全身施用表达IFN-β的MSC导致原发癌生长的抑制和肺和肝转移的显著减少。5)经MSC-IFN-β处理的小鼠（而非对照小鼠）的脾脏成熟树突状细胞（DC）、CD 8 + T细胞和CD 4 +/Foxp 3+调节性T细胞（Treg）维持正常水平。我们的研究结果表明，MSC能够在免疫活性环境中迁移到肿瘤部位，MSC产生的IFN-β通过抑制Stat 3信号传导抑制乳腺癌生长，并显着减少肺和肝转移。
We previously demonstrated that mesenchymal stem/stromal cells (MSC) are recruited to tumors and that IFN-beta produced by MSC inhibited tumor growth in xenograft models. Because of a deficient immune system, murine xenograft models cannot fully recapitulate tumor and immune cell interactions during progression. Therefore we investigated the capacity of MSC to migrate to and engraft into primary breast tumor sites and subsequently explore mechanisms of tumor inhibition by MSC-delivered IFN-beta in a syngeneic, immunocompetent murine model. Herein we report that 1) systemically administrated MSC migrate to established 4 T1 breast cancer sites and localize among the tumor-stroma border and throughout the tumor mass; 2) high levels of IFN-beta secreted by MSC are detectable in the tumor microenvironment but not in circulation; 3) intratumorally produced IFN-beta inactivates constitutive phos-phorylation of signal transducer activator transcription factor 3 (Stat3), Src, and Akt and down-regulates cMyc and MMP2 expression in 4 T1 cells, and 4) in mice with established breast cancer IFN-beta expressing MSC administered systemically resulted in inhibition of primary cancer growth and in dramatic reduction of pulmonary and hepatic metastases. 5) MSC-IFN-beta treated, but not control mice, maintained normal levels of splenic mature dendritic (DC), CD8+ T cells and CD4+/Foxp3+ regulatory T-cells (Treg). Our findings suggest that MSC are capable of migrating to tumor sites in an immunocompetent environment, that IFN-beta produced by MSC suppresses breast cancer growth through inhibition of Stat3 signaling, and dramatically reduces pulmonary and hepatic metastases.