Author/Authors :
Wolf، نويسنده , , Monika Julia and Hoos، نويسنده , , Alexandra and Bauer، نويسنده , , Judith and Boettcher، نويسنده , , Steffen and Knust، نويسنده , , Markus and Weber، نويسنده , , Achim and Simonavicius، نويسنده , , Nicole K. Schneider، نويسنده , , Christoph JG Lang، نويسنده , , Matthias and Stürzl، نويسنده , , Michael and Croner، نويسنده , , Roland S. and Konrad، نويسنده , , Andreas and Manz، نويسنده , , Markus G. and Moch، نويسنده , , Holger and Aguzzi، نويسنده , , Adriano and van Loo، نويسنده , , Geert and Pasparakis، نويسنده , , Manolis and Prinz، نويسنده , , Marco and Borsig، نويسنده , , Lubor and Heikenwalder، نويسنده , , Mathias، نويسنده ,
Abstract :
Summary
sed 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.
