Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2+Ly6Chi 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.
Highlights
► Tumor-cell derived CCL2 controls vascular permeability, extravasation, and metastasis ► Endothelial CCR2 expression is necessary and sufficient for extravasation/ metastasis ► Activation of JAK2-Stat5 and p38MAPK signaling via CCR2 induce vascular permeability ► CCL2 expression levels correlate with metastatic potential of UICC IV colon carcinoma