We have shown that streptozotocin (Sz) inhibits pancreatic cancer induction by N-nitrosobis(2-oxopropyl)amine (BOP) in Syrian hamsters. This inhibitory effect of Sz was not abolished after insulin administration, indicating that the inhibition of cancer induction in Sz-diabetic hamsters was not related to the lack of insulin. From these findings, we hypothesize that other islet hormones, such as insulinlike growth hormone (IGF-I), islet cells per se by their paracrine function or the Sz-induced diabetic condition (hyperglycemia, ketonemia, etc.), interact with pancreatic carcinogenesis. To validate our hypothesis, we propose two experiments. In Experiment 1, we will transplant 1,000 homologous islets of female hamsters into the left submandibular gland (SMG) and cultured normal hamster pancreatic ductal cells (as control cell) into the right SMG of 50 Sz-treated male Syrian hamsters, which will then be treated with BOP (10 mg/kg b.w.) weekly for 10 weeks. Forty control male hamsters will receive islets transplanted into their renal capsule and will be treated with BOP as above. If islet cells are involved in carcinogenesis, ductal/ductular tumors will develop in the left SMG with transplanted islets but no tumors will show in the right SMG with transplanted pancreatic ductal cells, in the renal subcapsule or in the pancreas of these hamsters. We have shown that islets transplanted into the SMG of diabetic hamsters survive, grow and correct diabetes. Our pilot study has also shown that BOP induces ductal/ductular lesions in the SMG of hamsters after islet transplantation into their SMG. However, because in this pilot study we observed animals only for a short time, we do not know whether these lesions progress to frank carcinoma and whether these lesions show the same c-Ki-ras mutation as in the primary pancreatic cancer. We also do not know whether the lesions induced in the SMG arose from periinsular or intrainsular ductules of transplanted islets or from SMG ductules. These questions will be examined. In Experiment 2, we will wrap the pancreases of 50 male Sz-treated hamsters with cellophane strips to induce focal nesidioblastosis. Six weeks after the wrapping (when new islets have developed), hamsters will be treated with BOP as above. If intact islets are a prerequisite for cancer induction, tumors will develop primarily in the wrapped, islet-enriched area. We will examine the level of blood glucose, insulin and urinary glucose in all hamsters once before Sz- treatment and at various intervals thereafter. The patterns of alpha, beta, delta and pancreatic polypeptide cells will be examined in the pancreas and SMG by respective antibodies using immunohistochemistry. We also will examine the presence of Y chromosome in the lesions induced in the SMG to see if the tumors derive from the female (islet) or male (SMG) tissue. The results will help us to design studies to elucidate the mechanisms involved and to develop preventive measures.
Showing the most recent 10 out of 22 publications
