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
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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.
Cancer cell 07/2012; 22(1):91-105. · 25.29 Impact Factor
