Role of urokinase receptor in tumor progression and development

Abstract

Elevated level of urokinase receptor (uPAR) is detected in various aggressive cancer types and is closely associated with poor prognosis of cancers. Binding of uPA to uPAR triggers the conversion of plasminogen to plasmin and the subsequent activation of metalloproteinases. These events confer tumor cells with the capability to degrade the components of the surrounding extracellular matrix, thus contributing to tumor cell invasion and metastasis. uPA-uPAR interaction also elicits signals that stimulate cell proliferation/survival and the expression of tumor-promoting genes, thus assisting tumor development. In addition to its interaction with uPA, uPAR also interacts with vitronectin and this interaction promotes cancer metastasis by activating Rac and stimulating cell migration. Although underlying mechanisms are yet to be fully elucidated, uPAR has been shown to facilitate epithelial-mesenchymal transition (EMT) and induce cancer stem cell-like properties in breast cancer cells. The fact that uPAR lacks intracellular domain suggests that its signaling must be mediated through its co-receptors. Indeed, uPAR interacts with diverse transmembrane proteins including integrins, ENDO180, G protein-coupled receptors and growth factor receptors in cancer cells and these interactions are proven to be critical for the role of uPAR in tumorigenesis. Inhibitory peptide that prevents uPA-uPAR interaction has shown the promise to prolong patients' survival in the early stage of clinical trial. The importance of uPAR's co-receptor in uPAR's tumor-promoting effects implicate that anti-cancer therapeutic agents may also be developed by disrupting the interactions between uPAR and its functional partners.

Keywords: uPA; uPAR; urokinase receptor.

Figure 1

Role of uPAR in tumor progression and metastasis. Binding of uPA to uPAR facilitates uPA activation and subsequent initiation of protease cascade, which in turn results in the degradation of extracellular matrix proteins and tumor cells invasion. Binding of uPA and vitronectin also promotes cell adhesion and cell migration. The action of uPA-uPAR/vitronectin is terminated through its interaction with PAI-1/PN-1 that triggers the internalization of uPAR complex. In addition, uPAR also interacts with various cell surface receptors such as integrins, growth factor receptors and ENDO180. These interactions activate diverse signaling pathways including FAK, Src, MAPK and PI3K, leading to EMT, cell proliferation, cell migration and expression of pro-cancer genes. Together, uPAR plays an essential role in tumor progression and metastasis.