Hepatocellular neoplasms induced by low-number pancreatic islet transplants in streptozotocin diabetic rats.
We have previously demonstrated in short-term experiments that altered hepatocytes in liver acini draining the blood from intraportally transplanted pancreatic islets in streptozotocin-induced diabetic rats with mild persisting diabetes resemble those in preneoplastic foci of altered hepatocytes. We now present the results of long-term studies (up to 22 months) in this animal model. Glycogen-storing foci (which were the first parenchymal alteration observed some days after transplantation) persisted at least for 6 months, when the first mixed-cell foci and the first hepatocellular adenoma emerged. After 15 to 22 months, 86% of the animals exhibited at least one hepatocellular adenoma and four animals (19%) showed a hepatocellular carcinoma. The transplants were found in a close spatial relationship with the preneoplastic foci and the hepatocellular neoplasms. The mitotic indices, the 5-bromo-2'-desoxyuridine labeling indices and the apoptotic indices showed significant differences between the unaltered liver parenchyma, different types of preneoplastic foci, and hepatocellular neoplasms. The immunohistochemical expression of transforming growth factor-alpha increased during the stepwise development from glycogen-storing liver acini to hepatocellular carcinomas. Hepatocarcinogenesis in this new animal model is probably due to the hormonal and growth-stimulating effects of insulin secreted by the intraportally transplanted islets of Langerhans in diabetic rats.
Dombrowski
F
F
Pathologisches Institut, Universität Bonn, Germany.
Bannasch
P
P
Pfeifer
U
U
D000236:Adenoma / Q000209:etiology / Q000473:pathology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology*; D016022:Case-Control Studies; D002423:Cause of Death; D003593:Cytoplasm / Q000648:ultrastructure; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced*; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D007150:Immunohistochemistry; D016381:Islets of Langerhans Transplantation; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D013311:Streptozocin; D016211:Transforming Growth Factor alpha / Q000032:analysis
D001786:Blood Glucose; D016211:Transforming Growth Factor alpha; D013311:Streptozocin