Antitumor activity of targeting SRC kinases in endothelial and myeloid cell compartments of the tumor microenvironment.
Antitumor activity of targeting SRC kinases in endothelial and myeloid cell compartments of the tumor microenvironment.
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DOI：
10.1158/1078-0432.ccr-09-1486
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发表时间：
2010-02-01
期刊：
影响因子：
--
通讯作者：
Jove R
中科院分区：
文献类型：
--
作者：
Liang W;Kujawski M;Wu J;Lu J;Herrmann A;Loera S;Yen Y;Lee F;Yu H;Wen W;Jove R
几种Src家族激酶（SFK）抑制剂基于其对肿瘤细胞的直接作用而进入临床试验。在这里，我们描述了靶向Src激酶对肿瘤微环境的影响以及这些影响如何影响肿瘤生长。用达沙替尼（一种SFKs的小分子抑制剂）处理在细胞培养物或小鼠中生长的人类癌细胞。分析肿瘤微环境中的肿瘤细胞、内皮细胞和髓样细胞区室。在细胞培养物中用达沙替尼处理原代人内皮细胞和新鲜分离的小鼠CD 11b +/CD 11 c −髓样细胞。评价了受达沙替尼影响的细胞功能和信号通路。达沙替尼在细胞培养中对此处研究的人癌细胞系无细胞毒性。然而，在人荷瘤小鼠中给予达沙替尼可抑制肿瘤生长，并伴有肿瘤细胞凋亡增加、微血管密度降低和肿瘤内CD 11b+髓样细胞减少。达沙替尼直接抑制内皮细胞和骨髓细胞的运动性和其他功能，同时抑制SFKs的磷酸化和下游信号传导。肿瘤浸润性骨髓细胞被确定为肿瘤微环境中MMP-9的主要来源。达沙替尼治疗通过同时抑制MMP 9+髓样细胞的募集和肿瘤浸润髓样细胞中MMP-9基因表达来降低肿瘤微环境中的MMP-9水平。这些发现表明，Src激酶抑制剂如达沙替尼具有以前未被认识到的抗癌作用机制，其靶向肿瘤微环境中的宿主来源的内皮细胞和骨髓细胞区室。
Several Src family kinase (SFK) inhibitors have entered clinical trials based on their direct effects against tumor cells. Here we characterize the effects of targeting Src kinases on the tumor microenvironment and how these effects influence tumor growth. Human cancer cells grown in cell culture or in mice were treated with dasatinib, a small-molecule inhibitor of SFKs. Tumor cell, endothelial cell and myeloid cell compartments within the tumor microenvironment were analyzed. Primary human endothelial cells and freshly-isolated CD11b+/CD11c− myeloid cells from mice were treated with dasatinib in cell culture. Cellular functions and signaling pathways affected by dasatinib were evaluated. Dasatinib was not cytotoxic in cell culture against the human cancer cell lines investigated here. However, dasatinib administration in human tumor-bearing mice suppressed tumor growth associated with increased tumor cell apoptosis, decreased microvessel density and reduced intratumoral CD11b+ myeloid cells. Dasatinib directly inhibited motility and other functions of endothelial and myeloid cells, accompanied by inhibition of phosphorylation of SFKs and downstream signaling. Tumor-infiltrating myeloid cells were identified as the major source of MMP-9 in the tumor microenvironment. Dasatinib treatment reduced MMP-9 levels in the tumor microenvironment through simultaneous inhibition of recruitment of MMP9+ myeloid cells and MMP-9 gene expression in tumor-infiltrating myeloid cells. These findings suggest that Src kinase inhibitors like dasatinib possess a previously unrecognized anti-cancer mechanism of action by targeting both host-derived endothelial and myeloid cell compartments within the tumor microenvironment.