Abstract 1504: Characterization of the murine oral squamous cell carcinoma cell line AT84 stably overexpressing uPAR

Abstract

Abstract Cancers of the oral cavity are associated with poor prognosis, and almost half of the patients diagnosed with oral squamous cell carcinoma (SCC) will die from the disease. Compared to its counterpart in skin, one main differing feature is the ability of oral SCC to metastasize. A prerequisite for metastasis is the capability to invade the surrounding tissue and penetrate into the nearest blood- or lymphatic vessel. This initial step in metastasis requires several extracellular matrix degrading enzymes. One such enzyme is uPA (urokinase-type plasminogen activator), involved in pericellular proteolysis, where high levels are correlated with poor prognosis in several cancers. Upon binding of pro-uPA to its extracellular receptor uPAR, the enzyme is cleaved and activated. uPA further activates matrix metalloproteases (MMP's), also needed for matrix degradation. In addition, ample evidence shows that binding of uPA to uPAR triggers receptor-mediated cellular signaling. uPAR lacks a membrane spanning domain hence signal transduction has to be mediated through one or several membrane partners. uPARs role in the regulation of cell adhesion, migration and proliferation has been linked to its interplay with membrane partners such as integrins, EGFR, caveolin and G-protein coupled receptors (e.g. FPRL1). To better understand the role of uPAR in the invasive growth and metastasis of oral SCCs, the mouse oral SCC cell line, AT84 [1, 2], was stably transfected with uPAR. Overexpression of uPAR resulted in down regulation of epithelial marker E-cadherin and the cells display a more mesenchymal appearance, indicating epithelial-mesenchymal transition (EMT). In addition, elevation of uPAR expression increased migration in a wound healing assay. In contrast to previous reports, an increase in MMP-9 activity was not observed in these cells, although an increase in overall proteolytic activity could be found using gelatin as substrate. The cells were reintroduced into the C3H mouse to observe the role of uPAR in cancer progression in vivo. Results from the analysis of the host-tumor interactions within this syngenous mouse model will be presented. 1. Lou, E., et al., Clinical and pathological features of the murine AT-84 orthotopic model of oral cancer. Oral Dis, 2003. 9(6): p. 305-12. 2. Schultz-Hector, S. and S. Haghayegh, Beta-fibroblast growth factor expression in human and murine squamous cell carcinomas and its relationship to regional endothelial cell proliferation. Cancer Res, 1993. 53(6): p. 1444-9. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1504. doi:10.1158/1538-7445.AM2011-1504