Transformation of a non-secretory neuroendocrine tumor to insulinoma after treatment with Sunitinib: A case report and review of the literature.

We report a case of a non-secretory neuroendocrine tumor which transformed into an insulin secreting tumor after treatment with Sunitinib. To our knowledge, this has only been described in three other cases worldwide. Previously reported case series find transformation of non-secretory neuroendocrine cancers into secretory lesions occurs in 3.4-6.8% of cases. Sunitinib is known to have the potential to lower blood glucose and induce epigenetic changes in cells of various types. We hypothesize that the mechanism for Sunitinib-induced transformation in cancer phenotype is through epigenetic changes in DNA expression within the tumor cells.

Insulin modulates glucose-dependent insulinotropic polypeptide (GIP) secretion from enteroendocrine K cells in rats.

Effects of insulin excess and deficiency on glucose-dependent insulinotropic polypeptide (GIP) was examined in rats following insulinoma transplantation or streptozotocin (STZ) administration. Over 14 days, food intake was increased (p < 0.001) in both groups of rats, with decreased body weight (p < 0.01) in STZ rats. Non-fasting plasma glucose levels were decreased (p < 0.01) and plasma insulin levels increased (p < 0.001) in insulinoma-bearing rats, whereas STZ treatment elevated glucose (p < 0.001) and decreased insulin (p < 0.01). Circulating GIP concentrations were elevated (p < 0.01) in both animal models. At 14 days, oral glucose resulted in a decreased glycaemic excursion (p < 0.05) with concomitant elevations in insulin release (p < 0.001) in insulinoma-bearing rats, whereas STZ-treated rats displayed similar glucose-lowering effects but reduced insulin levels (p < 0.01). GIP concentrations were augmented in STZ rats (p < 0.05) following oral glucose. Plasma glucose and insulin concentrations were not affected by oral fat, but fat-induced GIP secretion was particularly (p < 0.05) increased in insulinoma-bearing rats. Exogenous GIP enhanced (p < 0.05) glucose-lowering in all groups of rats accompanied by insulin releasing (p < 0.001) effects in insulinoma-bearing and control rats. Both rat models exhibited increased (p < 0.001) intestinal weight but decreased intestinal GIP concentrations. These data suggest that circulating insulin has direct and indirect effects on the synthesis and secretion of GIP.

Improved activity of streptozotocin-selected insulinoma cells following microencapsulation and transplantation into diabetic mice.

We have recently shown that repeated streptozotocin (STZ) treatment induces the selection of insulinoma cells (RINmS) with both improved resistance to diabetogenic toxins and functional activity, compared to parental RINm cells. The aim of the present study was to estimate the potential of RINmS cells to maintain their engineered characteristics during in vivo hyperglycemic conditions. It was found that microencapsulation and transplantation into diabetic mice preserved a three-fold higher level of insulin content in selected RINmS cells when compared to the parental ones. Retrieval of transplanted encapsulated cells from the peritoneal cavity of diabetic mice had a significantly higher insulin content and a more intense insulin response to secretogogues in selected RINmS cells when compared to retrieved RINm cells. In conclusion, our results show that RINmS cells do not lose their improved functional characteristics after encapsulation and transplantation into diabetic mice.

Peripheral nerve pathology in rats with streptozotocin-induced insulinoma.

Peripheral nerve structure was systematically examined in rats with insulinoma induced by streptozotocin (STZ). Normal Wistar rats, aged 3 months (n = 10), were treated with intravenous injections of STZ (20 mg/kg) and housed in plastic cages with free access to water and chow until 24 months of age. Three rats with insulinoma survived and were examined pathologically. Age-matched normal Wistar rats (n = 6) were used for comparison. The insulinoma-bearing rats showed a marked increase in body weight and decrease in blood glucose. In a teased nerve fiber study of the sciatic nerve, the percentage of abnormal fibers undergoing axonal degeneration and de- and remyelination in age-matched normal control rats was 3.9 +/- 2.5% (means +/- SD), whereas in the three insulinoma-bearing rats 49%, 50%, and 24%, respectively, of the fibers showed such changes. Regenerating fibers were also numerous in each insulinoma-bearing rat (36%, 42% and 27%, respectively). Morphometric analysis revealed smaller mean myelinated fiber and axonal areas in all the nerves examined (sciatic, tibial and sural) in insulinoma-bearing rats as compared to those in age-matched normal rats. Fiber area frequency histograms showed a decrease in large myelinated fibers and an increase in small regenerated fibers in insulinoma-bearing rats. Ultrastructurally, endoneurial microvessels exhibited a narrowed vascular lumen with swollen endothelial cells and vacuolar degeneration of pericytes, suggesting an involvement of vascular changes in the neuropathic development. The present study demonstrated marked structural changes in both motor and sensory peripheral nerves of rats bearing experimentally induced insulinoma. We consider that axonal degeneration, regeneration and demyelination constitute the main pathology in the peripheral nerves of insulinoma-bearing rats, although no particular difference in severity of the lesions between sensory and motor and between proximal and distal nerves was apparent.

Insulinoma after streptozotocin therapy for metastatic gastrinoma: natural history or iatrogenic complication?

Islet cell carcinoma frequently produces more than one chemical product, although its clinical expression is usually restricted to a single hormone. We describe an unusual patient who presented with full-blown metastasizing gastrinoma. He was treated with cimetidine for five years and then streptozotocin therapy, which resulted in a regression in hepatomegaly and a fall in serum gastrin levels. Following one year's therapy with streptozotocin, he was admitted in hyperinsulinemic hypoglycemic stupor. This appears to be the first reported case of a "shift" from clinical gastrinoma to insulinoma possibly related to prolonged streptozotocin therapy.

Inhibition of streptozotocin-induced islet cell tumors and N-nitrosobis(2-oxopropyl)amine-induced pancreatic exocrine tumors in Syrian hamsters by exogenous insulin.

The effects of streptozotocin (SZ) and N-nitrosobis(2-oxopropyl)amine (BOP), separately or in combination, on the pancreas, common duct, and gallbladder, all target tissues of BOP, were studied in Syrian golden hamsters. Groups of hamsters were treated with either a single dose (20 mg/kg body weight) of BOP (BOP group), or a single i.p. dose (50 mg/kg body weight) of SZ and 14 days later with a single s.c. injection of the same dose of BOP (SZ + BOP group). Another group of animals was treated similarly with BOP and SZ except that they received twice daily injections of insulin, beginning 1 day after SZ administration and for the duration of the experiment (52 weeks) (SZ + insulin + BOP group). The control group consisted of hamsters treated with a single dose of BOP and daily doses of insulin (insulin + BOP group). Hamsters treated with SZ recovered spontaneously from their diabetes, although the mortality was high (86%). BOP treatment inhibited the diabetogenic effects of SZ in both SZ + BOP and SZ + insulin + BOP groups and reduced the mortality to 43 and 74%, respectively. SZ pretreatment inhibited the incidence of BOP-induced pancreatic ductal/ductular cell carcinomas in the SZ + BOP group (P less than 0.01); this protective effect of SZ on carcinoma development was potentiated by additional treatment with insulin (SZ + insulin + BOP group, P less than 0.001). Although the frequency of BOP-induced tumors in the gallbladder (all polyps) was not altered by either SZ or insulin, the frequency of the common duct polyps was significantly lower in the SZ + insulin + BOP group than in the BOP group (P less than 0.005). Hamsters in the SZ, SZ + BOP, and SZ + insulin + BOP groups developed islet cell adenomas (insulomas). However, the SZ + insulin + BOP group had significantly fewer insulomas than in the SZ + BOP group (P less than 0.0005). The overall data confirm the inhibitory effect of SZ on BOP-induced pancreatic cancer and suggest that this effect is related to the diabetic condition of hamsters rather than insulin deficiency and that intact islets appear to be prerequisite for exocrine pancreatic cancer induction by BOP. On the other hand, the inhibitory action of insulin on insuloma induction by SZ and on ductal/ductular cancer induction by BOP seems to be related to the suppressive effect of this hormone on beta-cell and ductal/ductular cell replication, respectively.

Expression of the insulinoma gene rig during liver regeneration and in primary cultured hepatocytes.

We have isolated a novel gene, rig (rat insulinoma gene) from rat insulinomas. In the present study, rig was found to be expressed in rat regenerating liver and in primary cultured rat hepatocytes. The level of rig mRNA was increased at the proliferative phase of liver regeneration. In synchronously cultured hepatocytes, the rig mRNA level was elevated at the G1 phase of the cell cycle and the rig-protein was accumulated in the nuclei during the S phase. These results indicated that rig could be involved in a more general way in growth or cell replication.

Induction of rat pancreatic B-cell tumors by the combined administration of streptozotocin or alloxan and poly(adenosine diphosphate ribose) synthetase inhibitors.

Streptozotocin and alloxan were administered to Wistar rats in combination with poly(adenosine diphosphate ribose) synthetase inhibitors. Ten to 16 months after the injection of streptozotocin (50 mg/kg body weight i.v.) and 3-aminobenzamide (345 mg/kg i.v.), streptozotocin (50 mg/kg) and nicotinamide (350 mg/kg i.p.), streptozotocin (50 mg/kg) and picolinamide (250 mg/kg i.p.), alloxan (40 mg/kg i.v.) and nicotinamide (350 mg/kg), alloxan (40 mg/kg) and 3-aminobenzamide (345 mg/kg), and alloxan (40 mg/kg) and picolinamide (250 mg/kg), pancreatic islet cell tumors developed in 100, 98, 60, 26, 22, and 20% of surviving rats, respectively. However, after the single injection of streptozotocin and alloxan, islet cell tumors developed in 42 and 11% of surviving rats, respectively. The tumors were rich in B-granules on electron micrographs and contained as large amounts of proinsulin messenger RNA as normal pancreatic islets. The results indicate that poly(adenosine diphosphate ribose) synthetase inhibitors enhance the tumorigenic effect of streptozotocin and alloxan on islet B-cells.

On the histogenesis of experimental pancreatic endocrine tumors. An immunocytochemical and electron microscopical study.

In order to identify the early stage of the development of experimental pancreatic endocrine tumors, Wistar rats were treated with streptozotocin and nicotinamide. One to 11 months after the treatment, the pancreata were examined for neoplastic lesions, using immunocytochemistry and electronmicroscopy. The earliest changes consisted of focal adenomatous proliferation of small ducts, occasionally including endocrine cell clusters. They occurred in the same frequency throughout the whole period examined, regardless whether the pancreata contained tumors or not, and were also present, though in lower numbers, in controls. Immunocytochemistry revealed no true budding off of endocrine cells from ductular epithelium. Thus the histogenetic relationship of the ductal proliferations to the endocrine tumors remains unclear. The earliest tumors were recognized at the fourth month. At the eleventh month 31% of the animals beared tumors. Insulin-positive cells predominated in the tumors, followed by somatostatin-, glucagon- and PP-positive cells. The multihormonal appearance of the neoplasmas is well comparable with the findings in human insulinomas.

Interaction of dietary fat and protein on pancreatic carcinogenesis in Syrian golden hamsters.

The role of interactions between dietary fat and protein in experimental pancreatic cancer was determined in Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two levels of corn oil [4.5 and 18 g/385 kilocalorie (kcal)] were fed with each of two levels of casein (9 g/385 kcal and 36 g/385 kcal), either before or after a single sc injection of BOP (10 mg/kg body wt) at 8 weeks of age. Control diet was fed at other times (9 g corn oil and 18 g casein/385 kcal). The pancreatic ductular carcinoma incidence and multiplicity (average No. of tumors/tumor-bearing animals) increased as dietary fat and protein levels rose in hamsters fed the four diets after carcinogen treatment. Enhanced carcinogenesis by high-fat (HF) diets occurred only in hamsters fed the high-protein (HP) level, and protein effects were seen only with the HF diets. The low-fat-low-protein (LF-LP) diet inhibited pancreatic carcinogenesis among the hamsters given the four diets before BOP treatment. Pancreatic adenoma yields were elevated in hamsters given either HF or HP diets following BOP treatment, by comparison with the low levels. However, when diets were fed before BOP treatment, an increased yield occurred with the rise in protein, but the yield was reduced in males with the increase in fat. Acinar cell nodules were observed primarily in hamsters fed LP levels after BOP, and their multiplicity was highest in those given the HF diet. The interaction between dietary fat and protein demonstrated the interdependence of the effects of these two nutrients on pancreatic carcinogenesis in hamsters.

Neoplastic lesions in streptozotocin-treated rats.

Pathological examination was carried out on 16 male Sprague-Dawley rats received single i. v. injection of 60 mg/kg of streptozotocin (SZ) at 5 weeks of age and maintained for 22 months. Insulinoma (63%), renal adenoma (50%), hepatocellular tumor (69%), cholangioma (31%) and Leydig cell tumor (56%) were found in a high incidence, and therefore occurrence of these tumors was considered to be attributable to the treatment with SZ. In addition to these tumors, though in a low incidence, various such tumors as leukemia, reticulum cell sarcoma, mammary tumor and glioma were also found.