Hormonal regulation of sex differentiated liver carcinogenesis in the rat

Abstract: Endocrine factors influence cancer development in a variety of reproductive and non-reproductive tissues and organs. The incidence of liver cancer is higher in men than in women and long-term administration of androgens and estrogens has been reported to increase the risk for liver cancer formation, supporting the importance of hormonal factors in the etiology of this tumor. Hormonal effects on liver carcinogenesis have been demonstrated also in experimental animals. In the resistant hepatocyte model (RH-model), a multistage system of rat liver carcinogenesis, the male predominant tumor induction has been shown to be introduced during the promotion stage and to be controlled by the hypothalamic-pituitary-liver axis, via the sexual dimorphism in the secretory pattern of growth hormone (GH). Male predominant promotion with deoxycholic acid has also been shown to be regulated by the GH secretory pattern. This thesis aimed to further study the role of the hypothalamic-pituitary-liver axis in sex differentiation of rat liver carcinogenesis at different stages. Initiation with diethylnitrosamine was found to cause pituitary damage and long-lasting disturbance of endocrine control of sex differentiated liver functions. Also the initiation process could be sex differentiated and regulated by the GH secretory pattern, depending on the carcinogen used. In the RH-model, the GH regulation of male predominant promotion with 2-acetylaminofluorene and partial hepatectomy might be achieved partly by a direct effect on growth control in the putatively preneoplastic hepatic foci, in addition to an effect on mitoinhibition of the surrounding tissue. A persistent hormone-regulated change in growth control of foci might be programmed during promotion. Male predominant promotion with a choline-deficient diet was regulated by GH, like that seen with 2-acetylaminofluorene. Thus choline-deficiency represents a third example of GH-regulated promoting regimens. GH regulation of c-myc gene expression was indicated as part of the molecular basis for the sex differentiated promotion. During progression in the RH-model persistent liver nodules and hepatocellular carcinomas from both male and female rats showed decreased expression of the liver-enriched CCAAT/enhancer binding protein alpha (C/EBPa), C/EBPb, hepatocyte nuclear factor-l (HNF-I) and HNF-4, compared to the adjacent tissue. These decreases might contribute to development of the resistance phenotype of nodules, but might not be related to the establishment of sex differentiation in the resistance phenotype. Furthermore, advanced male nodules showed a normal response to GH. Thus the alterations in several sex differentiated parameters of liver functions in the nodules are not due to withdrawal from the normal endocrine control. Taken together, this thesis has illustrated more clearly some of the cellular and molecular events with respect to sex differentiation occurring during different stages of rat liver carcinogenesis. A better understanding of these events will hopefully improve our understanding of hormonal regulation of the development of human liver cancer.