Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer
Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer
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DOI：
10.1002/ijc.27735
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发表时间：
2013-02-15
影响因子：
6.4
通讯作者：
Chayama, Kazuaki
中科院分区：
文献类型：
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作者：
Shinagawa, Kei;Kitadai, Yasuhiko;Chayama, Kazuaki
据报道，骨髓来源的间充质干细胞（MSCs）有助于肿瘤促进基质细胞的形成。我们最近报道，在原位结肠癌裸鼠模型中，MSCs向肿瘤间质转移，并分化为癌相关成纤维细胞（CAF）样细胞。我们还发现，cas高水平表达血小板衍生生长因子受体（PDGFR），并且针对cas中PDGFR的伊马替尼治疗可抑制人结肠癌的生长和转移。这些发现使我们研究了伊马替尼阻断PDGFR信号传导是否会损害MSCs的促肿瘤作用。人骨髓间充质干细胞与KM12SM人结肠癌细胞原位移植和脾注射，与单独移植KM12SM细胞相比，对肿瘤生长和肝转移的促进作用明显更大。KM12SM + MSC异种移植物增强细胞增殖和血管生成，抑制肿瘤细胞凋亡。当荷瘤动物接受伊马替尼治疗时，尽管进行了KM12SM+MSC异种移植，但原发肿瘤体积或肝转移的总体积均未显著增加，混合细胞组的生存时间因伊马替尼治疗而延长。此外，MSCs向肿瘤间质迁移的能力受损，在肿瘤微环境中存活的MSCs数量明显减少。在体外实验中，伊马替尼抑制了MSCs的迁移。我们的数据表明，PDGF信号通路的阻断会影响肿瘤微环境中骨髓来源的MSCs与肿瘤细胞之间的相互作用，从而抑制结肠癌的进行性生长。
Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to formation of tumor-promoting stromal cells. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells. We also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor-promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. Orthotopic transplantation and splenic injection of human MSCs along with KM12SM human colon cancer cells, in comparison with transplantation of KM12SM cells alone, resulted in significantly greater promotion of tumor growth and liver metastasis. The KM12SM + MSC xenograft enhanced cell proliferation and angiogenesis and inhibited tumor cell apoptosis. When tumor-bearing animals were treated with imatinib, there was no significant increase in primary tumor volume or total volume of liver metastases, despite the KM12SM+MSC xenograft, and survival in the mixed-cell group was prolonged by imatinib treatment. Moreover, the ability of MSCs to migrate to tumor stroma was impaired, and the number of MSCs surviving in the tumor microenvironment was significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration of MSCs. Our data suggest that blockade of PDGF signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer.