CCL2 Is a Vascular Permeability Factor Inducing CCR2-Dependent Endothelial Retraction during Lung Metastasis

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F19%3A00071048" target="_blank" >RIV/00159816:_____/19:00071048 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14310/19:00107961

Výsledek na webu

<a href="https://mcr.aacrjournals.org/content/17/3/783" target="_blank" >https://mcr.aacrjournals.org/content/17/3/783</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1158/1541-7786.MCR-18-0530" target="_blank" >10.1158/1541-7786.MCR-18-0530</a>

Jazyk výsledku

angličtina

Název v původním jazyce

CCL2 Is a Vascular Permeability Factor Inducing CCR2-Dependent Endothelial Retraction during Lung Metastasis

Popis výsledku v původním jazyce

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 endothelialspecific Ccr2-deficient mouse model (Ccr2(ec)KO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2(ec)KO and Ccr2(fl/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 Ccr2(ec)KO and Ccr2(fl/f)l littermates the absence of vascular permeability induction was observed only in Ccr2(ec)KO 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.

Název v anglickém jazyce

CCL2 Is a Vascular Permeability Factor Inducing CCR2-Dependent Endothelial Retraction during Lung Metastasis

Popis výsledku anglicky

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 endothelialspecific Ccr2-deficient mouse model (Ccr2(ec)KO). Similar levels of circulating monocytes and equal leukocyte recruitment to metastatic lesions of Ccr2(ec)KO and Ccr2(fl/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 Ccr2(ec)KO and Ccr2(fl/f)l littermates the absence of vascular permeability induction was observed only in Ccr2(ec)KO 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

<a href="/cs/project/GJ17-08985Y" target="_blank" >GJ17-08985Y: Prozánětlivá signalizace pod kontrolou proteinu c-Myb v bazálních prsních karcinomech</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

MOLECULAR CANCER RESEARCH

ISSN

1541-7786

e-ISSN

—

Svazek periodika

17

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

783-793

Kód UT WoS článku

000460099800012

EID výsledku v databázi Scopus

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