The overall goal of this application is to elucidate the mechanisms that regulate the expression of proteoglycan genes in cancer, especially during the formation of tumor stroma, a vital source of nutrients and growth- supportive factors. The central hypothesis is that the structural, compositional and molecular changes of proteoglycans in cancer stroma are not random events, but rather are the result of specific interactions between neoplastic and host mesenchymal cells. Proteoglycans are major constituents of this tumor matrix and play pivotal roles not only in matrix assembly, but also in the sorting, storing and delivering of growth factors/cytokines. Aberrant expression of the two extracellular matrix proteoglycans, decorin and versican, would contribute to tumor promotion and invasion by providing a well-hydrated and growth factor-enriched microenvironment. The major goals for the next five years are to determine the molecular organization of decorin and versican genes, to investigate the functional activity of their respective promoters using recombinant DNA and gene transfer techniques, and to generate transgenic animals overexpressing or lacking these two important genes.
The specific aims are to: (1) Determine whether altered decorin and versican gene expression correlates with invasive behavior of human colon cancer, (2) Determine the complete genomic structure of decorin and versican genes, identify cis-acting DNA regulatory elements in their promoters and test their functional activities using heterologous gene constructs and transient transfection assays, (3) Generate stable transfectants of human colon cancer cells expressing high levels of decorin or versican proteoglycans, and characterize tumorigenicity of the transfectants both in vitro and in vivo, and (4) Develop transgenic mice overexpressing or lacking decorin and versican genes. These concerted research lines will provide information on the structural and functional organization of decorin and versican genes and should firmly establish their roles in tumorigenicity. The development of transgenic animals with viral-induced overexpression or targeted disruption of these two important genes should provide novel avenues of research and possibly unravel unexpected functions for these two proteoglycans. The results could lead to future approaches of cancer prevention and treatment directed at hindering the expression of these two proteoglycans thereby depriving the tumor cells of essential macromolecules.
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