[Frontiers in Bioscience 2, d271-282, June 1, 1997]

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Parviz M. Pour

The UNMC/Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE

Received 5/6/97 Accepted 6/2/97


Several studies have addressed whether pancreatic tumors produce diabetogenic substances. In one study, extracts of pancreatic cancer tissue inhibited glycogen synthesis in the rat muscle in vitro (87). However, this study did not clarify whether the diabetogenic substance(s) was produced by the tumor cells, by the endocrine cells admixed with tumor cells, or by the functionally altered islets near the tumor. The study by Del Favero et al. indicated that the tumor cells may be the source of these substances (88). When extracts of the human pancreatic cancer cell line, MIA PaCa2, were injected into immunodeficient mice daily for 40 days, the animals became hyperglycemic (88).

The role of IAPP in the causation of diabetes in pancreatic cancer patients is suggested by its inhibition of glucose uptake and glycogen synthesis in skeletal muscle in vitro and in vivo, and in the liver in vivo (85,89,90). IAPP also inhibits food intake. In rats, IAPP induces nearly a 48% decrease in food intake and a 7.2% weight loss within 72 hours (90). Consequently, the high serum levels of IAPP in pancreatic cancer patients may contribute to cachexia, profound insulin resistance, and diabetes (85).

Recent results refute the previous notion that diabetes is a risk factor for pancreatic cancer. These clinical and experimental results were confirmed by a recent epidemiological survey (91), where a correlation was made between 19 types of cancers and diabetes mellitus. The study showed a significant risk factor for liver, pancreas, and endometrial cancers. However, when the time of the diagnosis of diabetes in these patients was taken into consideration, the relative risk for liver and endometrial cancers remained elevated up to 10 years or more after the diagnosis of diabetes. In contrast, for pancreatic cancer, the relative risk for this cancer declined from 3.2 in the 5 years since diagnosis of diabetes, to 2.3 in the 5­9 years after diagnosis, and to 1.3 in the 10 or more years after the diagnosis of diabetes. Based on these data, the investigators concluded that diabetes mellitus could be a causative factor in the development of liver and endometrial cancers, while diabetes may be an early symptom rather than a direct cause of pancreatic cancer, or at least preneoplastic pancreatic lesions (91). These results parallel the clinical observations showing that development of diabetes or altered glucose tolerance occurs shortly before the clinical manifestation of pancreatic cancer (79,80,92). The lack of type I diabetic patients among the 720 pancreatic cancer patients examined by Gullo et al. (79) is noteworthy.

Nevertheless, the recent studies, which need further refinement and confirmation, indicate that pancreatic cancer is not merely a disease of the exocrine pancreas. The experimental results clearly show and the clinical data indicate that pancreatic ductal adenocarcinoma also arise from within islets, most probably from undifferentiated cells which also give rise to tumors that originate from ductal epithelium. However, it is noteworthy that in both the experimental model and in humans, tumors arising from large ducts, i.e., intraductal tumors, have a slow grow rate and considerably better prognosis (93), while the most common type, ductal adenocarcinoma, most probably arising from within islets, is malignant and fatal. The reason for the fast growth and expansion of tumors arising from within islets could well be related to a suitable environment within islets, where high concentrations of the growth factors, insulin, TGF-a, and IGF-1 are present.