PMC:4135037 / 9538-13002 JSONTXT

{"project":"2_test","denotations":[{"id":"24531709-11158604-79171864","span":{"begin":294,"end":295},"obj":"11158604"},{"id":"24531709-11158604-79171864","span":{"begin":294,"end":295},"obj":"11158604"},{"id":"24531709-12819299-79171864","span":{"begin":294,"end":295},"obj":"12819299"},{"id":"24531709-12819299-79171864","span":{"begin":294,"end":295},"obj":"12819299"},{"id":"24531709-19620250-79171864","span":{"begin":294,"end":295},"obj":"19620250"},{"id":"24531709-19620250-79171864","span":{"begin":294,"end":295},"obj":"19620250"},{"id":"24531709-17416457-79171865","span":{"begin":1971,"end":1973},"obj":"17416457"},{"id":"24531709-17416457-79171865","span":{"begin":1971,"end":1973},"obj":"17416457"},{"id":"24531709-18663428-79171866","span":{"begin":1975,"end":1977},"obj":"18663428"},{"id":"24531709-18663428-79171866","span":{"begin":1975,"end":1977},"obj":"18663428"},{"id":"24531709-12917627-79171867","span":{"begin":2901,"end":2903},"obj":"12917627"},{"id":"24531709-12917627-79171867","span":{"begin":2901,"end":2903},"obj":"12917627"}],"text":"Pancreatic islet tumorigenesis in Men1+/− mice depends on Cdk4\nPrevious studies reported that 30-50% of Men1+/− mice exhibited tumors in the endocrine pancreas, mostly insulinomas, during 8-18 months of age, and almost 80% of Men1+/− mice developed islet adenomas or carcinomas by 18-26 months 3-5. To determine the effects of Cdk4 or Cdk2 deficiency on islet tumorigenesis, we examined pancreatic tissues from 15-month-old Men1+/−; Cdk4−/− mice, Men1+/−; Cdk2−/− mice and control littermates with Men1+/+ and/or Cdk wild-type genotypes. Histological analyses showed that 62% of Men1+/−; Cdk wild-type mice (n=29) had islet tumors (Fig. 2A, C). Of the samples examined, islet adenomas were found in 12 (67%) of 18 Men1+/−; Cdk wild-type females and 6 (55%) of 11 Men1+/−; Cdk wild-type males. Essentially all islet tumors displayed insulin immunoreactivity (Fig. 2B), indicating these were insulinomas. No glucagonomas were observed in the examined groups of mice. Spontaneous islet tumors could not be found in Men1+/+ mice regardless of the Cdk4 or Cdk2 genotypes. In sharp contrast to Men1+/−; Cdk wild-type mice, none of 30 Men1+/−; Cdk4−/− mice (19 females and 11 males examined) had islet tumors or showed evidence of dysplasia. Indeed, pancreatic islets of Men1+/−; Cdk4−/− mice were markedly hypoplastic, essentially identical in appearance to the hypoplasia in the islets of Men1+/+; Cdk4−/− mice. On the other hand, 10 (77%) of 13 Men1+/−; Cdk2−/− females and 12 (57%) of 21 Men1+/−; Cdk2−/− males exhibited islet tumors, again demonstrating the lack of restraining effect of Cdk2 deficiency on both normal growth of the islets and neoplastic transformation..\nWe then examined proliferation of islet cells using immunohistochemistry with the Ki67 proliferation marker (Fig. 3A, B). In normal islets of wild-type mice, approximately 0.2% of endocrine cells stained positive for Ki67 immunoreactivity (Fig. 3B, Group 1), which is consistent with previous reports 24, 25. In Men1+/−; Cdk wild-type mice, even islets that appeared normal in size showed higher percentages (0.7%) of Ki67-positive endocrine cells (Group 2). In hyperplastic or dysplastic Men1+/− islets, about 1.5% of cells showed Ki67 immunoreactivity (Group 3), and 6.5% of cells in islet adenomas were Ki67-positive (Group 4). In Men1+/−; Cdk4−/− islets and Men1+/+; Cdk4−/− islets, Ki67-positive endocrine cells were virtually undetectable (Group 5), indicating that the absence of CDK4 severely impaired proliferation of islet cells in adult mice. In Men1+/−; Cdk2−/− mice, 0.5%, 2.2% and 6.0% of cells were Ki67-positive in normal, hyperplastic/dysplastic and adenomatous islets, respectively (Groups 6-8). Thus, increased proliferation is correlated with tumorigenic changes in Men1+/− islets, regardless of the Cdk2 genotype. Previous studies showed that adult murine islets express relatively high levels of CDK4 protein 22, consistent with its role in β cell proliferation. Our immunohistochemical analysis not only confirmed readily detectable expression of CDK4 in wild-type and Cdk2−/−islets, but also demonstrated robust CDK4 expression in islet tumors of Men1+/−; Cdk wild-type and Men1+/−; Cdk2−/− mice (Fig. 3C). CDK4 expression was not detected in Cdk4−/− islets, confirming the specificity of the immunoreactivity. These data indicate that Cdk4 is required for islet tumorigenesis initiated by hemizygous loss of Men1, while Cdk2 function can be compensated in this process."}