Abstract
The expression of urokinase-type plasminogen activator (uPA) receptor (uPAR) correlates with the malignant phenotype of various cancers. The soluble form of uPAR (s-uPAR) is present in the circulation of cancer patients, but the role of s-uPAR in endothelial cell migration is poorly understood. Therefore, we examined the role of tumor-associated s-uPAR on endothelial cell motility and angiogenesis. Here, we present evidence that tumor-associated s-uPAR augments the migration of human umbilical vein endothelial cells (HUVECs). When grown on tumor-conditioned medium, the membrane fraction of HUVECs had increased localization of s-uPAR onto its cell membrane. Colocalization studies for GM1 ganglioside receptor and uPAR further demonstrated s-uPAR recruitment onto lipid rafts of HUVECs. Immunoblot analysis for uPAR in lipid raft fractions confirmed s-uPAR recruiting onto HUVECs' membrane. Further, s-uPAR induced Rac1-mediated cell migration while either function-blocking uPAR antibodies or dominant-negative mutant Rac1 expression in HUVECs-mitigated s-uPAR-enhanced cell migration. In addition, orthotopic implantation of uPAR-overexpressing cells resulted in a significant increase in circulating s-uPAR in blood serum and invasive nature of tumor and tumor vasculature in mice. Collectively, this data provide insight into tumor-associated s-uPAR-directed migration of endothelial cells and its subsequent influence on tumor angiogenesis.
Highlights
Angiogenesis is a physiological multistep process of new blood vessel formation from pre-existing blood vessels to furnish nutrients and oxygen to rapidly growing cells and is crucial for physiological growth, tissue healing, regeneration and tumor growth.[1]
The urokinase-type plasminogen activator (uPA)/uPAR system has a critical role in tumor vascular biology by facilitating cell migration and modulating angiogenesis.[8,32]
The present study is the first demonstration that illustrates the intricacies involved in the regulation of tumor-associated soluble form of uPAR (s-uPAR) in connection with migration and angiogenesis
Summary
Angiogenesis is a physiological multistep process of new blood vessel formation from pre-existing blood vessels to furnish nutrients and oxygen to rapidly growing cells and is crucial for physiological growth, tissue healing, regeneration and tumor growth.[1] Owing to lack of oxygen and other essential nutrients, tumor masses beyond 1–2 mm in diameter require angiogenesis for their survival and progressive growth This process is regulated by a tight balance between pro- and anti-angiogenic agents, and involves a cascade of events of which the migration of capillary endothelial cells is an essential component.[1,2] The endothelial cell motile process is directionally regulated by chemotactic, haptotactic and mechanotactic stimuli, and further involves the degradation of the extracellular matrix to enable progression of the migrating cells.[3] For migration, endothelial cells need to be set free from their inherent location by losing cell–cell contacts and to be polarized to focus the newly formed proteolytic machinery at the leading edge, which is essential for the matrix degradation. In an in vitro angiogenic assay,[24] UR-CM elicited
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