Squamous cell carcinomas (SCC) are among the leading malignant cancers in the United State. During the last decade, studies have significantly advanced our understanding of the pathogenesis of this malignant disease;however, critical questions remain regarding the molecular mechanisms involved in angiogenesis, invasion and metastasis. Our long-range goal is to gain insight into the angiogenetic and invasive properties of SCC cells so that appropriate therapeutic interventions can be designed to improve therapeutic outcomes. The objective of this proposal is to determine mechanistically the involvement of two important extracellular matrix proteins of laminins-8 and -10 in SCC angiogenesis and metastases. We hypothesize that these two laminins play key roles in SCC angiogenesis and that laminin-10 is required by SCC cell invasion and metastasis. We plan to test our hypotheses by pursuing following two specific aims: 1. Determine the roles of laminin-8 and laminin-10 in human SCC tumor angiogenesis. The ability of these two molecules to promote cell attachment, migration and capillary tubule formation of blood vessel endothelial cells and the cell surface receptors responsible for these interactions will be determined. 2. Determine the functions of laminin-10 in SCC invasion and metastasis. The correlation of the laminin-10 expression and SCC progression will be established. The roles of laminin-10 in supporting SCC cell proliferation or survival, cell migration, invasion and metastasis will also be determined. Significance: These studies will provide insight into mechanisms of laminins -8 and -10 in SCC tumor angiogenesis and spreading, which will ultimately contribute to the development of novel therapies directed at these extracellular matrix molecules to alter SCC progression and to improve the outcomes of tumor therapy. The results obtained from this study will also provide useful information regarding the potential use of laminin-10 as a marker for the diagnosis/prognosis of SCC malignant potential. Additionally, what is learned from this study is expected to contribute to a broader understanding of other critical biological processes mediated by blood vessels, such as inflammation and wound healing, and how these laminins might be used as a novel approach to the therapy of other solid tumors that require a blood supply.
