Abstract
The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis.
Highlights
Over the last two decades, it became clear that tumor vascularization occurs through two distinct but complementary processes, namely, neoangiogenesis and vasculogenesis (the de novo formation of blood vessels through the mobilization and recruitment of Endothelial Progenitor Cells (EPCs) into the developing vasculature) [1,2]
Several studies identified Junctional Adhesion Molecule-C (JAM-C) as one of the molecules involved in the multistep process of leukocyte recruitment to inflammatory tissues, in particular during the transmigration process [20,23,25,28]
The recruitment of Endothelial Progenitor Cells (EPCs) to sites of tumor angiogenesis is a multistep process, and JAM-C was demonstrated in several studies to play a role
Summary
Over the last two decades, it became clear that tumor vascularization occurs through two distinct but complementary processes, namely, neoangiogenesis (the sprouting and remodeling of pre-existing blood vessels) and vasculogenesis (the de novo formation of blood vessels through the mobilization and recruitment of Endothelial Progenitor Cells (EPCs) into the developing vasculature) [1,2]. Using mouse embryonic-Endothelial Progenitor Cells (e-EPCs) [7], we previously demonstrated that their recruitment during tumor angiogenesis in vivo is a multistep process that requires a coordinated sequence of events, similar to leukocyte recruitment to inflammatory tissues [8]. The process comprises the activation of the tumor endothelium, arrest and firm adhesion to the endothelium, transendothelial extravasation into the interstitial space, perivascular formation of cellular clusters and interaction of e-EPCs with the angiogenic tumor vasculature [8]. Similar findings were recapitulated using human cord blood-derived EPCs [12]
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