Journal
CANCER CELL
Volume 22, Issue 1, Pages 91-105Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.05.023
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Funding
- ERC
- Helmholtz foundation
- Hofschneider foundation
- Oncosuisse
- Swiss National Foundation [310030130822, 31003A-133025]
- center of chronic immunodeficiency (CCI)
- DFG [SFB 620, FOR1336, PR 577/8-1]
- German Federal Ministry for Education and Research
- Swiss National Science Foundation (SNF) [31003A_133025] Funding Source: Swiss National Science Foundation (SNF)
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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.
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