Endothelial CCR2 Signaling Induced by Colon Carcinoma Cells Enables Extravasation via the JAK2-Stat5 and p38MAPK Pathway

被引：236

作者：

Wolf, Monika Julia ^{[2
]}

Hoos, Alexandra ^{[1
,5
]}

Bauer, Judith ^{[6
]}

Boettcher, Steffen ^{[3
]}

Knust, Markus ^{[7
,8
,9
]}

Weber, Achim ^{[4
]}

Simonavicius, Nicole ^{[6
]}

Schneider, Christoph ^{[10
]}

Lang, Matthias ^{[7
,8
]}

Stuerzl, Michael ^{[11
]}

Croner, Roland S. ^{[11
]}

Konrad, Andreas ^{[11
]}

Manz, Markus G. ^{[3
]}

Moch, Holger ^{[4
]}

Aguzzi, Adriano ^{[2
]}

van Loo, Geert ^{[12
]}

Pasparakis, Manolis ^{[13
,14
]}

Prinz, Marco ^{[7
,8
]}

Borsig, Lubor ^{[5
]}

Heikenwalder, Mathias ^{[2
]}

机构：

[1] Univ Zurich, Inst Physiol, Zurich Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland

[2] Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland

[3] Univ Zurich Hosp, Div Hematol, CH-8091 Zurich, Switzerland

[4] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland

[5] Univ Zurich, Zurich Ctr Integrat Human Physiol, Inst Physiol, CH-8057 Zurich, Switzerland

[6] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany

[7] Univ Freiburg, Dept Neuropathol, D-79106 Freiburg, Germany

[8] Univ Freiburg, BIOSS Ctr Biol Signaling Studies, D-79106 Freiburg, Germany

[9] Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany

[10] Swiss Fed Inst Technol, Inst Integrat Biol, CH-8952 Schlieren, Switzerland

[11] Univ Hosp Erlangen, Dept Surg, Div Mol & Expt Surg, D-91054 Erlangen, Germany

[12] VIB Gent, Dept Mol Biomed Res, B-9052 Ghent, Belgium

[13] Univ Cologne, Inst Genet, Ctr Mol Med CMMC, D-50674 Cologne, Germany

[14] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50674 Cologne, Germany

来源：

CANCER CELL | 2012年 / 22卷 / 01期

基金：

瑞士国家科学基金会;

关键词：

CHEMOKINE RECEPTOR 2; INFLAMMATORY MONOCYTES; TUMOR-METASTASIS; MYELOID CELLS; CANCER-CELLS; L-SELECTIN; MICE; CCL2; MIGRATION; LUNG;

D O I：

10.1016/j.ccr.2012.05.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：91 / 105

页数：15

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