PANCREATIC CANCER PREVENTION BY CALORIE RESTRICTION

胰腺癌是美国第五大癌症致死原因

Pancreatic cancer is the fifth leading cause of death by cancer in the United States. Its prognosis is dismal and little is known regarding prevention of this disease. Previous studies from this laboratory showed a delay in pancreatic ductular cancer in hamsters fed a slightly reduced calorie intake. Proposed studies will directly investigate the influence of calorie restriction on pancreatic cancer in the bis- 2(oxopropyl)nitrosamine (BOP) induced model of pancreatic cancer in the syrian hamster. This model of pancreatic cancer is particularly relevant to human pancreatic cancer. We have found an increase in the binding of the lectins L-PHA (from red kidney beans) and LEL (from tomatoes), and antibodies to Blood Group A antigens in tumor cell membranes and in cell lines isolated from pancreatic ductular carcinomas in comparison with normal pancreas. Such changes represent increased expression of oligosaccharide structures associated with the tumorigenic and metastatic phenotype. Our earlier investigations on calorie restriction and skin carcinogenesis demonstrated an inhibition of protein kinase C (PKC) activity in epidermal cells from the skin of mice fed calorie restricted diets. This observation may be important in the inhibition of cancer by dietary restriction because PKC has been identified as the receptor of the phorbol ester tumor promoters and as important in cell proliferation and differentiation pathways. The specific aims of this proposal are: 1) Determine the influence of graded calorie restriction on pancreatic carcinogenesis in the hamster model using BOP as the initiator. Diets restricted to 90%, 80% and 60% of the control calorie intake will be fed beginning one week following initiation with BOP until the end of the study. Hamsters will be held for 100-120 weeks depending upon the rate of development of cancer. 2) Assess the influence of calorie restriction on the metastatic potential of the tumors developing in the hamster pancreas. The expression of cell-surface oligosaccharides associated with the metastatic phenotype will be examined in tumors in normal and in restricted hamsters. 3) The influence of calorie restriction on protein kinase C isozyme levels and cellular and subcellular distribution will be determined by immune histochemistry in the pancreas. Hamsters will be prefed control and calorie restricted diets for 6-10 weeks before comparison of PKC levels. The proposed studies will demonstrate if calorie restriction can prevent pancreatic carcinogenesis and reduce the metastatic potential of tumors that do develop. Our results will also assess if the inhibition of pancreatic carcinogenesis by calorie restriction could be caused by reduction in duct cell PKC.