Nutritional manipulation of circadian rhythms and cancer

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DESCRIPTION (provided by applicant): Circadian rhythmicity provides a critically important temporal framework for many molecular, cellular and organismal functions. Until recently it was thought that circadian rhythms in mammals were generated by a single 'master oscillator' in the brain, the SCN. We now know that virtually all cells and tissues have molecular machinery capable of generating circadian rhythms. Several recent reports suggest that experimental manipulation of host circadian rhythmicity affects tumor growth and mortality in rodents with cancer. In humans there are indications that altered circadian rhythmicity correlates with risk of cancer and with survival statistics in diagnosed patients. Therefore the role played by circadian rhythms in host and tumor cells in the development of cancer is of great interest. Restricted feeding schedules synchronize circadian rhythms in behavior, physiology and gene expression in digestive organs was also shown to inhibit growth of Glasgow osteosarcoma and to slow associated mortality in mice. Therefore we propose a project to develop a better understanding of the impact of restricted feeding schedules on cancer prevention and development and tumor rhythmicity in liver. We will develop a new model to study the role of molecular circadian rhythms in the ontogeny and progression of hepatocellular carcinoma (HCC). Rats bearing the reporter gene Per1-luciferase will be administered Diethylnitrosamine (DENA). We will then expose these rats to daytime, nighttime, or non-circadian restricted feeding schedules. Tumor development will be assessed once per month by small-bore MRI and by mortality. In parallel we will assess the effects of each nutritional manipulation on clock gene expression patterns in healthy liver and in liver tumors. These studies will test the hypothesis that rhythmicity in peripheral structures is intimately related to the organism's ability to combat the development and progression of cancer. The experiments will form the basis for future study of circadian and nutritional influences on development of this and other cancers.