Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Cancer Cell. 2012 Jul 10;22(1):91-105. doi: 10.1016/j.ccr.2012.05.023.
Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
肿瘤细胞中趋化因子 CCL2 的表达增加与转移增强、预后不良以及 CCR2(+)Ly6C(hi)单核细胞的募集相关。然而，驱动肿瘤细胞穿过血管内皮细胞外渗的机制仍不清楚。在这里，我们描述了转移性 UICC Ⅳ期结肠癌中 CCL2 的上调，并证明肿瘤细胞衍生的 CCL2 激活了 CCR2(+)内皮细胞，从而增加了体内的血管通透性。CCR2 缺陷可防止结肠癌细胞外渗和转移。值得注意的是，耐辐射细胞上的 CCR2 表达或内皮细胞上的 CCR2 表达可恢复 Ccr2(-/-)小鼠的外渗和转移。髓样细胞上 CCR2 表达的减少会降低但不能防止转移。CCL2 诱导的血管通透性和转移依赖于 JAK2-Stat5 和 p38MAPK 信号通路。我们的研究确定了治疗 CCL2 依赖性转移的潜在靶点。
