Ling Xiaoyang, Marini Frank, Konopleva Marina, Schober Wendy, Shi Yuexi, Burks Jared, Clise-Dwyer Karen, Wang Rui-Yu, Zhang Weiguo, Yuan Xiaoqing, Lu Hongbo, Caldwell Lisa, Andreeff Michael
Molecular Hematology and Therapy Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030-4009 USA.
Cancer Microenviron. 2010 Mar 19;3(1):83-95. doi: 10.1007/s12307-010-0041-8.
We previously demonstrated that mesenchymal stem/stromal cells (MSC) are recruited to tumors and that IFN-β 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-β 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-β secreted by MSC are detectable in the tumor microenvironment but not in circulation; 3) intratumorally produced IFN-β inactivates constitutive phosphorylation 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-β expressing MSC administered systemically resulted in inhibition of primary cancer growth and in dramatic reduction of pulmonary and hepatic metastases. 5) MSC-IFN-β 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-β produced by MSC suppresses breast cancer growth through inhibition of Stat3 signaling, and dramatically reduces pulmonary and hepatic metastases.
The online version of this article (doi:10.1007/s12307-010-0041-8) contains supplementary material, which is available to authorized users.
我们之前证明间充质干/基质细胞（MSC）可被募集至肿瘤部位，且在异种移植模型中，MSC产生的IFN-β可抑制肿瘤生长。由于免疫系统缺陷，小鼠异种移植模型无法完全重现肿瘤进展过程中肿瘤与免疫细胞的相互作用。因此，我们研究了MSC迁移至并植入原发性乳腺肿瘤部位的能力，随后在同基因、具有免疫活性的小鼠模型中探究了MSC递送的IFN-β抑制肿瘤的机制。在此我们报告：1）全身给药的MSC迁移至已形成的4T1乳腺癌部位，并定位于肿瘤-基质边界及整个肿瘤块中；2）在肿瘤微环境中可检测到MSC分泌的高水平IFN-β，但在循环系统中未检测到；3）肿瘤内产生的IFN-β使信号转导激活因子转录因子3（Stat3）、Src和Akt的组成型磷酸化失活，并下调4T1细胞中cMyc和MMP2的表达；4）在已患乳腺癌的小鼠中，全身给予表达IFN-β的MSC可抑制原发性肿瘤生长，并显著减少肺和肝转移。5）经MSC-IFN-β处理的小鼠而非对照小鼠，脾脏成熟树突状细胞（DC）、CD8 + T细胞和CD4 + /Foxp3 +调节性T细胞（Treg）维持正常水平。我们的研究结果表明，MSC能够在具有免疫活性的环境中迁移至肿瘤部位，MSC产生的IFN-β通过抑制Stat3信号传导抑制乳腺癌生长，并显著减少肺和肝转移。
本文的在线版本（doi:10.1007/s12307-010-0041-8）包含补充材料，授权用户可获取。
