The overall objective of this renewal grant is to analyze the process of liver carcinogenesis in a well defined model of nutritional deficiency and to gain a better understanding of the mechanisms of nutritional modifications of cancer development. Choline deficiency leads to a variety of pathological lesions due to a decrease in phospholipid and acetylcholine synthesis and in the supply of labile methyl groups. Co-carcinogenic effect of a choline deficient (CD) diet on liver cancer induction is primarily mediated through its promoting action, though the debates as to the complete carcinogenicity of the diet per se persist. Several agents which modify the promoting efficacy of a CD diet have been identified, such as the quality of fat, hypolipidemic agents, methapyrilene, antioxidant and phenobarbital. A CD diet induces peroxidative damage of liver microsomal membrane lipids and the extent of lipid peroxidation modified by various agents was positively correlated with the efficacy of tumor promotion with the exception of phenobarbital. We postulate that one of the critical cellular changes relevant to tumor promotion resulting from the diet-induced lipid peroxidation may be functional alterations of the cell membranes. Our initial attempt indicated that there were changes in insulin receptors in CD-hepatocytes and hepatoma cells which may be one manifestation of broader alterations of cell membrane receptors involving cell growth control. We propose to extend our studies in several directions by evaluating i) effects of polyunsaturated fat have a high n-3 fatty acid content (fish oil) on CD promotion, ii) possible significance of the reported CD diet induced lipid peroxidation in nuclear fraction of hepatocytes, iii) the diet induced changes in selected membrane receptors for growth control (insulin, glucagon, insulin like growth factors and EGF) iv) receptor changes by different types of liver tumor promoters and v) sequential changes of growth factor receptors in preneoplastic and neoplastic lesions during CD promotion. These studies will provide critical information regarding possible consequences of the diet-induced membrane lipid peroxidation and its mechanistic significance related to liver tumor promotion.
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