Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway.
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.
Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Monika Julia
MJ
Wolf
Alexandra
A
Hoos
Judith
J
Bauer
Steffen
S
Boettcher
Markus
M
Knust
Achim
A
Weber
Nicole
N
Simonavicius
Christoph
C
Schneider
Matthias
M
Lang
Michael
M
Stürzl
Roland S
RS
Croner
Andreas
A
Konrad
Markus G
MG
Manz
Holger
H
Moch
Adriano
A
Aguzzi
Geert
G
van Loo
Manolis
M
Pasparakis
Marco
M
Prinz
Lubor
L
Borsig
Mathias
M
Heikenwalder
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D005119:Extravasation of Diagnostic and Therapeutic Materials; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases