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Endothelial CCR2 Promotes Pulmonary Metastasis


Roblek, Marko. Endothelial CCR2 Promotes Pulmonary Metastasis. 2015, University of Zurich, Faculty of Science.

Abstract

Nine out of ten cancer patients die due to metastasis. The generation of them is dependent on several factors, including the recruitment of inflammatory monocytes and activation of endothelial cells at the pre-metastatic niche. It is at these sites where cancer cell seeding of the targeted secondary tissue is taking place. Inflammatory chemokines, especially the chemokine ligand CCL2 and its receptor CCR2, are regulating several aspects of the metastatic cascade, including monocyte recruitment to the metastatic niche and induction of vascular permeability enabling cancer cell trans-endothelial migration. We aimed to target the CCL2-CCR2 signaling axis at the pre-metastatic niche by pharmacological inhibition and a genetic endothelial specific CCR2 knockout (CCR2ecKO) mouse model.
A mutant signaling deficient dnCCL2-HSA chimera strongly inhibited cancer cell trans-endothelial migration as well as cancer cell seeding to the lung. As a consequence the metastatic burden was strongly decreased in dnCCL2-HSA treated mice. The anti-metastatic effect of dnCCL2-HSA was dependent on its inhibition of cancer cell induced vascular permeability, while recruitment of inflammatory monocytes to the pre-metastatic niche was not impaired. dnCCL2-HSA was found to be present in close proximity to cancer cells in the lung vasculature, indicating that local inhibition of CCR2 signaling is sufficient to prevent metastasis initiation. Furthermore, targeting of cancer cell activated endothelial cells by VCAM-1 binding peptide equipped liposomes loaded with a CCR2 antagonist confirmed that inhibition of CCR2 at sites of activated endothelium is sufficient to prevent the generation of metastases. The spatial inhibition of CCR2 using these liposomes interfered with induction of vascular permeability, but spared any detectable effects on inflammatory monocytes. The endothelial specific CCR2 knockout (CCR2ecKO) mouse model confirmed findings from both inhibitor approaches. Spontaneous lung metastasis was strongly reduced in CCR2ecKO mice compared to control littermates. Leukocyte recruitment to the primary tumor, the pre-metastatic niche, and the metastatic environment however, was not affected due to the endothelial CCR2 knockout.Stimulation of endothelial cells with CCL2 caused phosphorylation of MLC2, which is required for endothelial cell retraction.
Overall we could show that endothelial CCR2 is the gatekeeper for cancer cell trans-endothelial migration and thus represents the final check-point for metastasis initiation of colon and lung cancer cells. Targeting endothelial CCR2 at pre-metastatic sites represents a promising treatment strategy to prevent cancer cell seeding and thus metastatic spread to the lung.

Abstract

Nine out of ten cancer patients die due to metastasis. The generation of them is dependent on several factors, including the recruitment of inflammatory monocytes and activation of endothelial cells at the pre-metastatic niche. It is at these sites where cancer cell seeding of the targeted secondary tissue is taking place. Inflammatory chemokines, especially the chemokine ligand CCL2 and its receptor CCR2, are regulating several aspects of the metastatic cascade, including monocyte recruitment to the metastatic niche and induction of vascular permeability enabling cancer cell trans-endothelial migration. We aimed to target the CCL2-CCR2 signaling axis at the pre-metastatic niche by pharmacological inhibition and a genetic endothelial specific CCR2 knockout (CCR2ecKO) mouse model.
A mutant signaling deficient dnCCL2-HSA chimera strongly inhibited cancer cell trans-endothelial migration as well as cancer cell seeding to the lung. As a consequence the metastatic burden was strongly decreased in dnCCL2-HSA treated mice. The anti-metastatic effect of dnCCL2-HSA was dependent on its inhibition of cancer cell induced vascular permeability, while recruitment of inflammatory monocytes to the pre-metastatic niche was not impaired. dnCCL2-HSA was found to be present in close proximity to cancer cells in the lung vasculature, indicating that local inhibition of CCR2 signaling is sufficient to prevent metastasis initiation. Furthermore, targeting of cancer cell activated endothelial cells by VCAM-1 binding peptide equipped liposomes loaded with a CCR2 antagonist confirmed that inhibition of CCR2 at sites of activated endothelium is sufficient to prevent the generation of metastases. The spatial inhibition of CCR2 using these liposomes interfered with induction of vascular permeability, but spared any detectable effects on inflammatory monocytes. The endothelial specific CCR2 knockout (CCR2ecKO) mouse model confirmed findings from both inhibitor approaches. Spontaneous lung metastasis was strongly reduced in CCR2ecKO mice compared to control littermates. Leukocyte recruitment to the primary tumor, the pre-metastatic niche, and the metastatic environment however, was not affected due to the endothelial CCR2 knockout.Stimulation of endothelial cells with CCL2 caused phosphorylation of MLC2, which is required for endothelial cell retraction.
Overall we could show that endothelial CCR2 is the gatekeeper for cancer cell trans-endothelial migration and thus represents the final check-point for metastasis initiation of colon and lung cancer cells. Targeting endothelial CCR2 at pre-metastatic sites represents a promising treatment strategy to prevent cancer cell seeding and thus metastatic spread to the lung.

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Additional indexing

Item Type:Dissertation
Referees:Müller A, Borsig Lubor
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:December 2015
Deposited On:05 Jan 2016 14:21
Last Modified:28 Jun 2016 10:21
Funders:SNSF

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