The active interplay between malignant and host mesenchymal cells leads to the formation of a tumor stroma which provides the infrastructures the tumor cells require for successful growth and infiltration. The central hypothesis of this research plan is that the formation of this matrix is a specialized process under the direct control of neoplastic cells and that changes in proteoglycan composition may ultimately affect neoplastic cell behavior. This hypothesis derives, in part, from our previous in vivo observations that chondroitin sulfate proteoglycan (CS-PG) is markedly increased in tissue extracts of human colon carcinoma and that the connective tissue stroma is the primary site of synthesis and accumulation of this gene product. Our subsequent studies have shown that colon carcinoma cells can modulate the biosynthesis of proteoglycans in human colon fibroblasts and smooth muscle cells by inducing the production of a CS-PG similar to that found in tissue extracts of colon carcinoma. The present research proposal is designed to explore further this complex phenomenon of tumor matrix production and to define some of the mechanisms that regulate its expression.
The specific aims are to: 1. Define the biochemical, structural and immunological characteristics of the protein core(s) of the proteoglycans synthesized by human colon smooth muscle cells and fibroblasts, and investigate changes induced by colon carcinoma cells. 2. Determine whether the stimulation of CS-PG is associated with increased levels of PG core specific mRNA, and whether these changes in mRNA levels reflect changes in transcription rates and/or RNA stability both in cultured cells and in colon carcinoma tissue. 3. Interfere with the process of excessive CS-PG production by depleting the intracellular pools of PG protein core or hexosamine, and determine key rate limiting factors of the transport, secretion and turnover of these gene products. The research should provide insights into the mechanisms by which rumor cells modulate PG metabolism in host mesenchymal cells. Potentially leading to future approaches of cancer prevention and treatment directed at hindering the formation of tumor stroma, thereby depriving the tumor cells of their essential support services.
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