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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026556-10
Application #
3167361
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1979-08-01
Project End
1992-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ledda-Columbano, G M; Columbano, A; Cannas, A et al. (1994) Dexamethasone inhibits induction of liver tumor necrosis factor-alpha mRNA and liver growth induced by lead nitrate and ethylene dibromide. Am J Pathol 145:951-8
Shinozuka, H; Kubo, Y; Katyal, S L et al. (1994) Roles of growth factors and of tumor necrosis factor-alpha on liver cell proliferation induced in rats by lead nitrate. Lab Invest 71:35-41
Smith, M L; Yeleswarapu, L; Lombardi, B et al. (1993) Lack of mutations of the p53 tumor suppressor gene in hepatocellular carcinomas induced in rats by a peroxisome proliferator. Mol Carcinog 7:89-93
Masuhara, M; Ogasawara, H; Katyal, S L et al. (1993) Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats. Carcinogenesis 14:1579-84
Masuhara, M; Katyal, S L; Nakamura, T et al. (1992) Differential expression of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in two experimental models of liver cell proliferation. Hepatology 16:1241-9
Yabu, K; Warty, V S; Shinozuka, H (1991) Cyclosporine enhances the growth of carcinogen-induced enzyme-altered foci in rat liver. Hepatology 13:304-9
Hsieh, L L; Shinozuka, H; Weinstein, I B (1991) Changes in expression of cellular oncogenes and endogenous retrovirus-like sequences during hepatocarcinogenesis induced by a peroxisome proliferator. Br J Cancer 64:815-20
Shinozuka, H; Warty, V S; Masuhara, M et al. (1991) Effect of FK 506 on experimental liver carcinogenesis. Transplant Proc 23:3197-9
Yokota, K; Singh, U; Shinozuka, H (1990) Effects of a choline-deficient diet and a hypolipidemic agent on single glutathione S-transferase placental form-positive hepatocytes in rat liver. Jpn J Cancer Res 81:129-34
Gupta, C; Banks, M; Shinozuka, H (1989) Elevated levels of prostaglandin E2 in the liver of rats fed a choline deficient diet: possible involvement in liver tumor promotion. Cancer Lett 46:129-35

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