Epithelial matrix in carcinoma development

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): Overview: The important roles that epithelial matrix interactions play in tumor invasion and tissue morphogenesis are just beginning to be understood. Data generated through our efforts during the previous funding cycle suggest important roles for laminin 5, bone morphogenic protein (BMP 1) isozymes and alpha 6 beta 4 integrin in squamous cell carcinoma (SCC) progression and an important role for laminin 10 in basal cell carcinoma (BCC) development. The current studies are directed at further defining the role of the extracellular matrix in development of non melanoma skin cancers. Through synergistic collaboration with the other Projects, the ultimate application of these studies will be to discover new molecular approaches to inhibit carcinoma development. They propose to: 1. Determine the roles of laminin 5 and beta 4 integrin in SCC progression. This Aim will determine the mechanisms by which laminin 5 and beta 4 integrin impact upon SCC tumors. They hypothesize that laminin 5 may inhibit and b4 integrin may promote SCC progression. This aim will utilize a Ras driven turnorigenesis model where keratinocytes are engineered to form SCC like tumors in immunodeficient mice. The effects of site directed mutagenesis of key domains on laminin 5 and beta 4 integrin cDNA will be examined in vivo for effects on SCC progression by in vitro and in vivo assays of cell and tumor invasion. Tumor size, morphology, differentiation, apoptosis and adhesion to host stroma will be evaluated. 2. Demonstrate the function of BMP I isozymes in SCC progression. Their preliminary results showed that BMP 1 isozyme mediated processing of laminin 5 supported SCC tumor invasion in vitro and characterized a potent and specific BMP 1 inhibitor with potential tumor inhibitory effects. In this Aim, they seek to extend these results to in vivo models of SCC tumor development. Expression of each of the four BMP 1 isozymes and the processing of laminin 5 will be evaluated in a survey of SCC tumors. The effect of BMP 1 isozyme mediated laminin 5 processing on SCC tumor progression will be studied through overexpression studies. Finally, specific BMP 1 isozyme inhibitors will be evaluated in vivo for their effects on tumor invasion. 3. Discover how laminins impact upon BCC development. Laminins perform important roles in tissue morphogenesis as well as carcinoma development. Their preliminary results show an important role for laminin 10 in hair development and suggest that laminin 10 supports BCC development as well. Additional studies suggest that laminin 5 may have an inhibitory effect on BCC. They will evaluate a number of tumor parameters in the study of the effects of laminin 10 inhibition in a BCC animal model. Multiple approaches will be utilized including the use of inhibitory antibodies and the use of laminin 5 mice. They will assess the effects of laminin 5 overexpression and underexpression on BCC development in an animal model using laminin 5 cDNAs delivered to primary and laminin 5 null EB keratinocytes.