Increased levels of the chemokine CCL2 in cancer patients are associated with poor prognosis. Experimental evidence suggests that CCL2 correlates with inflammatory monocyte recruitment and induction of vascular activation, but the functionality remains open. Here, we show that endothelial Ccr2 facilitates pulmonary metastasis using an endothelial-specific Ccr2-deficient mouse model (Ccr2ecKO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2ecKO and Ccr2fl/fl littermates were observed. The absence of endothelial Ccr2 strongly reduced pulmonary metastasis, while the primary tumor growth was unaffected. Despite a comparable cytokine milieu in Ccr2ecKO and Ccr2fl/fl littermates the absence of vascular permeability induction was observed only in Ccr2ecKO mice. CCL2 stimulation of pulmonary endothelial cells resulted in increased phosphorylation of MLC2, endothelial cell retraction, and vascular leakiness that was blocked by an addition of a CCR2 inhibitor. These data demonstrate that endothelial CCR2 expression is required for tumor cell extravasation and pulmonary metastasis. IMPLICATIONS: The findings provide mechanistic insight into how CCL2-CCR2 signaling in endothelial cells promotes their activation through myosin light chain phosphorylation, resulting in endothelial retraction and enhanced tumor cell migration and metastasis.

• MeSH
• chemokin CCL2 metabolismus   MeSH
• endoteliální buňky metabolismus   patologie   MeSH
• kapilární permeabilita MeSH
• karcinom plic Lewisové krevní zásobení   metabolismus   patologie   sekundární   MeSH
• lehké řetězce myosinu metabolismus   MeSH
• metastázy nádorů MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nádory plic krevní zásobení   metabolismus   patologie   sekundární   MeSH
• pohyb buněk fyziologie   MeSH
• receptory CCR2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Ccl2 protein, mouse MeSH Prohlížeč
• Ccr2 protein, mouse MeSH Prohlížeč
• chemokin CCL2 MeSH
• lehké řetězce myosinu MeSH
• receptory CCR2 MeSH