CXCR7 expression disrupts endothelial cell homeostasis and causes ligand-dependent invasion.
The homeostatic function of endothelial cells (EC) is critical for a number of physiological processes including vascular integrity, immunity, and wound healing. Indeed, vascular abnormalities resulting from EC dysfunction contribute to the development and spread of malignancies. The alternative SDF-1/CXCL12 receptor CXCR7 is frequently and specifically highly expressed in tumor-associated vessels. In this study, we investigate whether CXCR7 contributes to vascular dysfunction by specifically examining the effect of CXCR7 expression on EC barrier function and motility. We demonstrate that CXCR7 expression in EC results in redistribution of CD31/PECAM-1 and loss of contact inhibition. Moreover, CXCR7+ EC are deficient in barrier formation. We show that CXCR7-mediated motility has no influence on angiogenesis but contributes to another motile process, the invasion of CXCR7+ EC into ligand-rich niches. These results identify CXCR7 as a novel manipulator of EC barrier function via alteration of PECAM-1 homophilic junctions. As such, aberrant expression of CXCR7 in the vasculature has the potential to disrupt vascular homeostasis and could contribute to vascular dysfunction in cancer systems.
Vaccine and Gene Therapy Institute; Oregon Health and Science University; Portland, OR USA.
Jennifer E
JE
Totonchy
Vaccine and Gene Therapy Institute; Oregon Health and Science University; Portland, OR USA.
Lisa
L
Clepper
Department of Biomedical Engineering; Oregon Health and Science University; Portland, OR USA.
Kevin G
KG
Phillips
Department of Biomedical Engineering; Oregon Health and Science University; Portland, OR USA.
Owen J T
OJ
McCarty
Vaccine and Gene Therapy Institute; Oregon Health and Science University; Portland, OR USA.
Ashlee V
AV
Moses
D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D006801:Humans; D008024:Ligands; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D054387:Receptors, CXCR / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
C501896:ACKR3 protein, human; D008024:Ligands; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054387:Receptors, CXCR
CXCR7; ECIS; PECAM-1; cancer vascular dysfunction; endothelial cell adhesion; invasion