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 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.

• Authors: Monika Julia Wolf, Alexandra Hoos, Judith Bauer, Steffen Boettcher, Markus Knust, Achim Weber, Nicole Simonavicius, Christoph Schneider, Matthias Lang, Michael Stürzl, Roland S Croner, Andreas Konrad, Markus G Manz, Holger Moch, Adriano Aguzzi, Geert van Loo, Manolis Pasparakis, Marco Prinz, Lubor Borsig, Mathias Heikenwalder
• Journal: Cancer cell (Cancer Cell) Vol. 22 Issue 1 Pg. 91-105 (Jul 10 2012) ISSN: 1878-3686 [Electronic] United States
• PMID: 22789541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Ccr2 protein, mouse
• Receptors, CCR2
• STAT5 Transcription Factor
• JAK2 protein, human
• Janus Kinase 2
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cell Line, Tumor
• Colonic Neoplasms (metabolism, pathology)
• Extravasation of Diagnostic and Therapeutic Materials
• Janus Kinase 2 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, CCR2 (metabolism)
• STAT5 Transcription Factor (metabolism)
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)