The primary goal of this proposal is to establish the role of proteoglycans in tumor formation. Studies on the neoplastic behavior of proteoglycan-deficient mutants of Chinese hamster ovary (CHO) cells indicate that CHO cells require heparan sulfate proteoglycans to form subcutaneous tumors in nude mice. Additional experiments using other CHO cell mutants are proposed to learn more about the structural features of the proteoglycans required for tumor proliferation. Intravenous injection of cells should reveal if proteoglycans are also needed for tumor formation in the lungs, liver and other tissues. Transfection experiments in which proteoglycans foreign to CHO cells are expressed will help distinguish if core proteins or the glycosaminoglycan chains are required for tumor formation. As a corollary to these studies, compounds that inhibit proteoglycan synthesis will be tested as inhibitors of tumor formation. To gain insight into the organization and metabolism of tumor proteoglycans, chemical, radiochemical, and immunological studies of tumor proteoglycans derived from wild-type cells and mixtures of wild-type and mutant cells are proposed. Parallel studies of CHO cell aggregates will be conducted to examine if differences in proteoglycan metabolism in tumors and cells is due to cell aggregation. A long-range goal of this proposal is to determine whether viral transformation of CHO cells with Rous sarcoma virus affects the requirement for proteoglycans. To determine if other cells require proteoglycans for tumor formation, the isolation of mouse 3T3 cell mutants defective in proteoglycan synthesis will be attempted.
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