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Telomere dysfunction suppresses multiple endocrine neoplasia in mice.

Lee JH, Anver M, Kost-Alimova M, Protopopov A, DePinho RA, Rane SG - Genes Cancer (2014)

Bottom Line: Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN.We observed increased aneuploidy in Cdk4 (R/R) fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4 (R/R) islets and embryonic fibroblasts.Further, mTERC (-/-) Cdk4 (R/R) fibroblasts display reduced transformation potential.

View Article: PubMed Central - PubMed

Affiliation: Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD.

ABSTRACT
Multiple endocrine neoplasia (MEN) syndrome is typified by the occurrence of tumors in two or more hormonal tissues. Whereas the genetics of MEN syndrome is relatively well understood, the tumorigenic mechanisms for these cancers remain relatively obscure. The Cdk4 (R24C) mouse model develops highly penetrant pituitary tumors and endocrine pancreas adenomas, and, as such, this model is appropriate to gain insight into mechanisms underlying MEN. Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN. We observed increased aneuploidy in Cdk4 (R/R) fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4 (R/R) islets and embryonic fibroblasts. To better understand the role of telomerase, we generated Cdk4 (R24C) mice with inactivation of the mTERC locus, which codes for the essential RNA component of the enzyme telomerase (mTERC (-/-) Cdk4 (R/R) mice). Embryonic fibroblasts and islets derived from mTERC (-/-) Cdk4 (R/R) mice exhibit reduced telomere length and proliferative capacity. Further, mTERC (-/-) Cdk4 (R/R) fibroblasts display reduced transformation potential. Importantly, mTERC (-/-) Cdk4 (R/R) mice display significantly reduced spontaneous tumorigenesis. Strikingly, we observed dramatic suppression of pituitary tumors and endocrine pancreas adenomas in mTERC (-/-) Cdk4 (R/R) mice. Telomere dysfunction suppressed tumor initiation and increased latency of tumor development while not affecting the progression of established tumors. In summary, these results are suggestive of an important role for telomerase in tumor development in the Cdk4 (R24C) mouse model, specifically in the genesis of tumors in the pituitary and the endocrine pancreas.

No MeSH data available.


Related in: MedlinePlus

Tumor progression in Cdk4R/R pancreasH&E staining and immunostaining (brown) for insulin and β-catenin in different pancreatic tumor stages from 12-month old Cdk4R/R mice
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Figure 1: Tumor progression in Cdk4R/R pancreasH&E staining and immunostaining (brown) for insulin and β-catenin in different pancreatic tumor stages from 12-month old Cdk4R/R mice

Mentions: Cdk4 is essential for the post-natal development of pancreatic islet β-cells and proliferation of the anterior pituitary [19, 21, 22]. In contrast, the Cdk4R24C/R24C mice (Cdk4R/R mice) are susceptible to increased tumor development within the pituitary and the endocrine pancreas [23, 24]. To better stage the tumor progression, we performed histological analysis on pancreas sections from one-year old Cdk4R/R mice. These analyses revealed a distinct tumor development process in the endocrine pancreas; viz. (i) islet hyperplasia, (ii) islet adenomas, and infrequently, (iii) islet carcinomas (Figure 1). Abnormal localization of β-catenin is closely associated with carcinoma, tumor invasion and metastasis and poor survival and β-catenin localization is deregulated in human endocrine tumors [45]. β-catenin is transmembrane localized in normal cells, whereas in cancer cells, cytoplasmic or nuclear translocation of β-catenin is observed. Immunohistochemistry experiments indicated that β-catenin is localized to the membrane in hyperplastic endocrine islets in the Cdk4R/R pancreas (Figure 1), suggesting that majority of the cells at this stage were non-tumorigenic. In contrast, β-catenin was predominantly localized to the cytoplasm or nucleus in islet adenomas and rare islet carcinomas (Figure 1). Normal insulin immunoreactivity was observed in hyperplastic islets indicative of normal β-cell differentiation (Figure 1). In contrast, we observed a dramatic reduction of insulin staining in several regions within the islet adenomas and infiltrating islet carcinomas (Figure 1). Interestingly, we observed an inverse correlation between β-catenin localization and insulin expression. Normal insulin expressing cells within the hyperplastic islets exclusively contained membrane localized β-catenin. In contrast, the cytoplasmic or nuclear β-catenin observed in islet adenomas and carcinomas was accompanied with dramatic loss of insulin expression indicative of a tumorigenic transition.


Telomere dysfunction suppresses multiple endocrine neoplasia in mice.

Lee JH, Anver M, Kost-Alimova M, Protopopov A, DePinho RA, Rane SG - Genes Cancer (2014)

Tumor progression in Cdk4R/R pancreasH&E staining and immunostaining (brown) for insulin and β-catenin in different pancreatic tumor stages from 12-month old Cdk4R/R mice
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209601&req=5

Figure 1: Tumor progression in Cdk4R/R pancreasH&E staining and immunostaining (brown) for insulin and β-catenin in different pancreatic tumor stages from 12-month old Cdk4R/R mice
Mentions: Cdk4 is essential for the post-natal development of pancreatic islet β-cells and proliferation of the anterior pituitary [19, 21, 22]. In contrast, the Cdk4R24C/R24C mice (Cdk4R/R mice) are susceptible to increased tumor development within the pituitary and the endocrine pancreas [23, 24]. To better stage the tumor progression, we performed histological analysis on pancreas sections from one-year old Cdk4R/R mice. These analyses revealed a distinct tumor development process in the endocrine pancreas; viz. (i) islet hyperplasia, (ii) islet adenomas, and infrequently, (iii) islet carcinomas (Figure 1). Abnormal localization of β-catenin is closely associated with carcinoma, tumor invasion and metastasis and poor survival and β-catenin localization is deregulated in human endocrine tumors [45]. β-catenin is transmembrane localized in normal cells, whereas in cancer cells, cytoplasmic or nuclear translocation of β-catenin is observed. Immunohistochemistry experiments indicated that β-catenin is localized to the membrane in hyperplastic endocrine islets in the Cdk4R/R pancreas (Figure 1), suggesting that majority of the cells at this stage were non-tumorigenic. In contrast, β-catenin was predominantly localized to the cytoplasm or nucleus in islet adenomas and rare islet carcinomas (Figure 1). Normal insulin immunoreactivity was observed in hyperplastic islets indicative of normal β-cell differentiation (Figure 1). In contrast, we observed a dramatic reduction of insulin staining in several regions within the islet adenomas and infiltrating islet carcinomas (Figure 1). Interestingly, we observed an inverse correlation between β-catenin localization and insulin expression. Normal insulin expressing cells within the hyperplastic islets exclusively contained membrane localized β-catenin. In contrast, the cytoplasmic or nuclear β-catenin observed in islet adenomas and carcinomas was accompanied with dramatic loss of insulin expression indicative of a tumorigenic transition.

Bottom Line: Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN.We observed increased aneuploidy in Cdk4 (R/R) fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4 (R/R) islets and embryonic fibroblasts.Further, mTERC (-/-) Cdk4 (R/R) fibroblasts display reduced transformation potential.

View Article: PubMed Central - PubMed

Affiliation: Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD.

ABSTRACT
Multiple endocrine neoplasia (MEN) syndrome is typified by the occurrence of tumors in two or more hormonal tissues. Whereas the genetics of MEN syndrome is relatively well understood, the tumorigenic mechanisms for these cancers remain relatively obscure. The Cdk4 (R24C) mouse model develops highly penetrant pituitary tumors and endocrine pancreas adenomas, and, as such, this model is appropriate to gain insight into mechanisms underlying MEN. Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN. We observed increased aneuploidy in Cdk4 (R/R) fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4 (R/R) islets and embryonic fibroblasts. To better understand the role of telomerase, we generated Cdk4 (R24C) mice with inactivation of the mTERC locus, which codes for the essential RNA component of the enzyme telomerase (mTERC (-/-) Cdk4 (R/R) mice). Embryonic fibroblasts and islets derived from mTERC (-/-) Cdk4 (R/R) mice exhibit reduced telomere length and proliferative capacity. Further, mTERC (-/-) Cdk4 (R/R) fibroblasts display reduced transformation potential. Importantly, mTERC (-/-) Cdk4 (R/R) mice display significantly reduced spontaneous tumorigenesis. Strikingly, we observed dramatic suppression of pituitary tumors and endocrine pancreas adenomas in mTERC (-/-) Cdk4 (R/R) mice. Telomere dysfunction suppressed tumor initiation and increased latency of tumor development while not affecting the progression of established tumors. In summary, these results are suggestive of an important role for telomerase in tumor development in the Cdk4 (R24C) mouse model, specifically in the genesis of tumors in the pituitary and the endocrine pancreas.

No MeSH data available.


Related in: MedlinePlus