2012
DOI: 10.1016/j.ccr.2012.05.023
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Endothelial CCR2 Signaling Induced by Colon Carcinoma Cells Enables Extravasation via the JAK2-Stat5 and p38MAPK Pathway

Abstract: 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 m… Show more

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Cited by 264 publications
(282 citation statements)
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“…Disseminated cells may promote the trafficking of Ly-6C high monocytes to the skin and the activation and differentiation of Ly-6C high monocytes into inflammatory DCs, leading to the lysis of tumor cells and to the bystander destruction of normal melanocytes, thereby causing depigmentation. Until now, monocytic cells have been somehow considered as protumoral cells that facilitate metastatic spread by promoting tumor cell dissemination and dampening antitumor responses (44)(45)(46). Our results rather support that inflammatory monocytes are the most efficient effectors in controlling disseminated tumor cells.…”
Section: Discussionsupporting
confidence: 74%
“…Disseminated cells may promote the trafficking of Ly-6C high monocytes to the skin and the activation and differentiation of Ly-6C high monocytes into inflammatory DCs, leading to the lysis of tumor cells and to the bystander destruction of normal melanocytes, thereby causing depigmentation. Until now, monocytic cells have been somehow considered as protumoral cells that facilitate metastatic spread by promoting tumor cell dissemination and dampening antitumor responses (44)(45)(46). Our results rather support that inflammatory monocytes are the most efficient effectors in controlling disseminated tumor cells.…”
Section: Discussionsupporting
confidence: 74%
“…A survey of signalling pathways activated by SPARC-competent melanoma CM on endothelial cells identified the p38 MAPK pathway as responsible for tumour-induced actin cytoskeleton remodelling and intercellular pores formation. Activation of p38 MAPK signalling route in endothelial cells by extravasating tumour cells has been observed previously in colon carcinoma cells 34 . In our study, SPARC-mediated VCAM1 activation was found to stimulate SRC tyrosine kinase activity and p38-dependent MLC2 phosphorylation.…”
Section: Discussionsupporting
confidence: 64%
“…In this regard, CCL2 that we identified in our proteomic analysis, was recently shown to attract myeloidderived monocytes and to promote efficient colon cancer cell extravasation 34 . Whether metastasizing melanoma cells rely on SPARC for cooperative interactions with circulating blood cells enabling efficient extravasation across the vascular barrier remains to be determined.…”
Section: Discussionmentioning
confidence: 87%
See 1 more Smart Citation
“…61 In addition, CCL2 activates endothelial cells through the chemokine receptor CCR2 to increase vascular permeability and promote cancer cell extravasation and metastatic dissemination in a model of colon cancer. 62 In mouse models of lung metastasis, the inflammatory protein S100A8 induced serum amyloid A3 (SAA3) to activate NF-kB signaling via the toll-like receptor 4 (TLR4) in endothelial cells and macrophages. This resulted in high myeloid cell infiltration, and it accelerated the migration of primary tumor cells to lungs to form metastasis.…”
Section: Inflammation and Metastasismentioning
confidence: 99%