CCL2 Is a Vascular Permeability Factor Inducing CCR2-Dependent Endothelial Retraction during Lung Metastasis
| Autor: | Lubor Borsig, Cristina Stefanescu, Lucia Knopfová, Jesus Francisco Glaus Garzon, Darya Protsyuk, Christian Gorzelanny, Bruno Luckow, Marko Roblek, Stefan W. Schneider, Mathias Heikenwalder, Paul F. Becker |
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| Přispěvatelé: | University of Zurich, Borsig, Lubor |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CCR2 Chemokine Cancer Research Lung Neoplasms Myosin Light Chains Angiogenesis Receptors CCR2 animal diseases Vascular permeability 610 Medicine & health Article Metastasis 10052 Institute of Physiology Capillary Permeability 03 medical and health sciences Chemokine receptor Carcinoma Lewis Lung Mice 0302 clinical medicine Cell Movement parasitic diseases medicine 1312 Molecular Biology Animals 1306 Cancer Research Neoplasm Metastasis Molecular Biology Chemokine CCL2 Mice Knockout biology Chemistry Endothelial Cells hemic and immune systems medicine.disease Extravasation 3. Good health Endothelial stem cell Mice Inbred C57BL 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein 570 Life sciences 2730 Oncology |
| Zdroj: | Mol. Cancer Res. 17, 783-793 (2019) |
| ISSN: | 1557-3125 |
| Popis: | Increased levels of the chemokine CCL2 in cancer patients are associated with poor prognosis. Experimental evidence suggests that CCL2 correlates with inflammatory monocyte recruitment and induction of vascular activation, but the functionality remains open. Here, we show that endothelial Ccr2 facilitates pulmonary metastasis using an endothelial-specific Ccr2-deficient mouse model (Ccr2ecKO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2ecKO and Ccr2fl/fl littermates were observed. The absence of endothelial Ccr2 strongly reduced pulmonary metastasis, while the primary tumor growth was unaffected. Despite a comparable cytokine milieu in Ccr2ecKO and Ccr2fl/fl littermates the absence of vascular permeability induction was observed only in Ccr2ecKO mice. CCL2 stimulation of pulmonary endothelial cells resulted in increased phosphorylation of MLC2, endothelial cell retraction, and vascular leakiness that was blocked by an addition of a CCR2 inhibitor. These data demonstrate that endothelial CCR2 expression is required for tumor cell extravasation and pulmonary metastasis. Implications: The findings provide mechanistic insight into how CCL2–CCR2 signaling in endothelial cells promotes their activation through myosin light chain phosphorylation, resulting in endothelial retraction and enhanced tumor cell migration and metastasis. |
| Databáze: | OpenAIRE |
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