Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Cancer Res. 2013 Mar 15;73(6):1752-63. doi: 10.1158/0008-5472.CAN-12-2474. Epub 2013 Jan 17.
Ron receptor kinase (MST1R) is important in promoting epithelial tumorigenesis, but the potential contributions of its specific expression in stromal cells have not been examined. Herein, we show that the Ron receptor is expressed in mouse and human stromal cells of the prostate tumor microenvironment. To test the significance of stromal Ron expression, prostate cancer cells were orthotopically implanted into the prostates of either wild-type or Ron tyrosine kinase deficient (TK(-/-); Mst1r(-/-)) hosts. In TK(-/-) hosts, prostate cancer cell growth was significantly reduced as compared with tumor growth in TK(+/+) hosts. Prostate tumors in TK(-/-) hosts exhibited an increase in tumor cell apoptosis, macrophage infiltration and altered cytokine expression. Reciprocal bone marrow transplantation studies and myeloid cell-specific ablation of Ron showed that loss of Ron in myeloid cells is sufficient to inhibit prostate cancer cell growth. Interestingly, depletion of CD8(+) T cells, but not CD4(+) T cells, was able to restore prostate tumor growth in hosts devoid of myeloid-specific Ron expression. These studies show a critical role for the Ron receptor in the tumor microenvironment, whereby Ron loss in tumor-associated macrophages inhibits prostate cancer cell growth, at least in part, by derepressing the activity of CD8(+) T cells.
罗恩受体激酶 (MST1R) 在促进上皮肿瘤发生中很重要，但尚未研究其在基质细胞中特异性表达的潜在贡献。在此，我们显示罗恩受体在前列腺肿瘤微环境的小鼠和人类基质细胞中表达。为了测试基质 Ron 表达的意义，将前列腺癌细胞原位植入野生型或 Ron 酪氨酸激酶缺陷型 (TK(-/-); Mst1r(-/-)) 宿主的前列腺中。与 TK(+/+) 宿主中的肿瘤生长相比，在 TK(-/-) 宿主中，前列腺癌细胞的生长明显减少。在 TK(-/-) 宿主中，前列腺肿瘤中的肿瘤细胞凋亡增加、巨噬细胞浸润和细胞因子表达改变。相互的骨髓移植研究和髓样细胞特异性 Ron 缺失表明，髓样细胞中 Ron 的缺失足以抑制前列腺癌细胞的生长。有趣的是，耗尽 CD8(+) T 细胞而不是 CD4(+) T 细胞能够恢复在缺乏髓样特异性 Ron 表达的宿主中前列腺肿瘤的生长。这些研究表明 Ron 受体在肿瘤微环境中具有关键作用，其中肿瘤相关巨噬细胞中 Ron 的缺失通过去抑制 CD8(+) T 细胞的活性至少部分抑制了前列腺癌细胞的生长。
