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Selectin-driven leukocyte recruitment and chemokines facilitate metastasis


Hoos, Alexandra. Selectin-driven leukocyte recruitment and chemokines facilitate metastasis. 2013, University of Zurich, Faculty of Science.

Abstract

Tumor is a complex tissue composed of malignant and heterogeneous non-malignant cells. Tumor progression is determined by the dynamic interactions between these cells. Soluble factors secreted within the tumor microenvironment stimulate stromal cells and induce infiltration by inflammatory cells. High amounts of monocytes/macrophages, commonly found in various types of malignant cancer are associated with increased tumor cell extravasation and metastasis. A recent study reported that CCL2 recruits inflammatory monocytes to promote metastasis. Concerted action of chemokines and adhesion molecules (selectins) regulates the homing of leukocytes to target sites. However, the role of endogenous (non-tumor derived) selectin ligands in metastasis was not characterized. To study the contribution of endogenous selectin ligands to metastasis, we used Fuc-TVII-/- mice which display defective selectin ligands. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII-/- mice correlated with attenuated metastasis, suggesting the presence of endogenous selectin ligands on monocytes as a prerequisite for their capture at metastatic sites. Adoptive transfer of Fuc-TVII+ monocytes rescued metastasis, corroborating that monocyte recruitment is selectin ligand-dependent. Moreover, decreased CCL2 expression in Fuc-TVII deficient lung was linked to impaired monocyte recruitment, reduced tumor cell survival and attenuated metastasis. This study demonstrated that endogenous selectin ligands mediate the recruitment and activation of monocytes at the metastatic site and thereby facilitate metastasis. To delineate the molecular mechanism governing the effect of CCL2 on metastasis, we used different mouse models. Together with Monika Wolf, we demonstrated that CCR2 expression not only on monocytes, but in particular on the endothelium, is crucial for metastasis. Tumor cell-derived CCL2 induced vascular permeability and enabled efficient tumor cell extravasation via CCR2 signaling. The absence of CCR2 on the endothelium abolished tumor cell extravasation even in the presence of CCR2+ monocytes, highlighting that activation of CCR2 on the endothelium is a prerequisite for tumor cell migration. Collectively, our study identified a novel mechanism for CCL2-dependent metastasis.

Abstract

Tumor is a complex tissue composed of malignant and heterogeneous non-malignant cells. Tumor progression is determined by the dynamic interactions between these cells. Soluble factors secreted within the tumor microenvironment stimulate stromal cells and induce infiltration by inflammatory cells. High amounts of monocytes/macrophages, commonly found in various types of malignant cancer are associated with increased tumor cell extravasation and metastasis. A recent study reported that CCL2 recruits inflammatory monocytes to promote metastasis. Concerted action of chemokines and adhesion molecules (selectins) regulates the homing of leukocytes to target sites. However, the role of endogenous (non-tumor derived) selectin ligands in metastasis was not characterized. To study the contribution of endogenous selectin ligands to metastasis, we used Fuc-TVII-/- mice which display defective selectin ligands. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII-/- mice correlated with attenuated metastasis, suggesting the presence of endogenous selectin ligands on monocytes as a prerequisite for their capture at metastatic sites. Adoptive transfer of Fuc-TVII+ monocytes rescued metastasis, corroborating that monocyte recruitment is selectin ligand-dependent. Moreover, decreased CCL2 expression in Fuc-TVII deficient lung was linked to impaired monocyte recruitment, reduced tumor cell survival and attenuated metastasis. This study demonstrated that endogenous selectin ligands mediate the recruitment and activation of monocytes at the metastatic site and thereby facilitate metastasis. To delineate the molecular mechanism governing the effect of CCL2 on metastasis, we used different mouse models. Together with Monika Wolf, we demonstrated that CCR2 expression not only on monocytes, but in particular on the endothelium, is crucial for metastasis. Tumor cell-derived CCL2 induced vascular permeability and enabled efficient tumor cell extravasation via CCR2 signaling. The absence of CCR2 on the endothelium abolished tumor cell extravasation even in the presence of CCR2+ monocytes, highlighting that activation of CCR2 on the endothelium is a prerequisite for tumor cell migration. Collectively, our study identified a novel mechanism for CCL2-dependent metastasis.

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Additional indexing

Item Type:Dissertation
Referees:Müller A, Borsig L, Hennet T, Schwendener R
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:April 2013
Deposited On:05 Dec 2013 11:43
Last Modified:08 Dec 2017 00:41

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