BIOLOGY OF THE MOUSE HEPATOCARCINOGENESIS

本研究的目的是验证动态的假设

The objective of this study is to test the hypothesis that the dynamic phase of obesity, regardless of its cause, provides a stimulus to increase the growth rate of microscopic hepatocellular neoplasms in the mouse. The clinical implication is that patients who becomes obese after tumor initiation are at much greater risk for tumor growth stimulation that those who becomes obese prior to tumor initiation. Stereologic- computer based methods developed in this laboratory will be used to accurately determine the growth rates of large numbers of microscopic tumors that were initiated by single injections of diethylnitrosamine in 15 day old mice. The study will employ 3 different models of obesity induction (ovariectomy, ventromedial hypothalamic stereotactic injury, and feeding of highly palatable diet) which vary in the host's efficiency of energy use. The kinetics of tumor growth will be correlated with the rate of weight gain, and change in body composition (fat and protein) during the dynamic and stable phases of obesity development in the 3 models. Since true growth does not occur in the hypothalamic injury model, its study can help to distinguish the effects of carcass fat from protein deposition. A direct role of a decline in ovarian hormones in stimulating tumor growth will be studied by implanting ovaries into the spleens of carcinogen treated ovexed mice- a procedure which maintains a high level of portal blood hormones while reducing the systemic level. The more likely indirect effect of ovex will also be tested by constraining the food intake and weight gain of mice that are ovexed. The roles of changes in adipocyte number, size and lipoprotein lipase content, serum insulin and glucose, and receptors for insulin and EGF will also be studied as possible effects of the obesity stimulating effect of ovariectomy and hypothalamic injury.