[HTML][HTML] Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway

H Kawano, Y Ito, F Kanai, E Nakamura… - Oncology …, 2015 - spandidos-publications.com
H Kawano, Y Ito, F Kanai, E Nakamura, N Tada, S Takai, S Horie, T Kobayashi, O Hino
Oncology reports, 2015spandidos-publications.com
The model animal of renal cell carcinoma (RCC), the Eker rat, has a germline mutation in the
tuberous sclerosis 2 (Tsc2) gene. Heterozygous mutants develop RCCs by second hit in the
wild-type Tsc2 allele, whereas homozygous mutants are embryonic lethal. In the present
study, a new cell differentiation model was developed to study the mechanism of Tsc2
mutation-associated pathogenesis by generating Tsc2-deficient embryonic stem cells
(ESCs) from Eker rats. Tsc2+/+, Tsc2+/-and Tsc2-/-ESCs were all capable of generating …
Abstract
The model animal of renal cell carcinoma (RCC), the Eker rat, has a germline mutation in the tuberous sclerosis 2 (Tsc2) gene. Heterozygous mutants develop RCCs by second hit in the wild-type Tsc2 allele, whereas homozygous mutants are embryonic lethal. In the present study, a new cell differentiation model was developed to study the mechanism of Tsc2 mutation-associated pathogenesis by generating Tsc2-deficient embryonic stem cells (ESCs) from Eker rats. Tsc2+/+, Tsc2+/-and Tsc2-/-ESCs were all capable of generating three germ layers: mesoderm, ectoderm, and endoderm. Interestingly, epithelial tumor-like abnormal ductal structures were reproducibly observed in Tsc2-/-teratomas from different ESC lines. Immunohistochemical analysis revealed that mammalian target of rapamycin complex 1 (mTORC1) signaling was activated in abnormal ducts of Tsc2-/-teratomas, on the basis of positive staining for p-S6 and p-4EBP1. In these abnormal ducts, expression levels of epithelial markers (ie, megalin and cubilin) and the cytoplasmic localization of E-cadherin and β-catenin were similar to those in Eker rat RCCs. Moreover, a transcription factor regulated by mTORC1, named TFE3, was located in the nuclei of abnormal ducts and Eker rat RCCs. As a negative regulator of ESC differentiation, TFE3 may result in tissue-specific differentiation defects related to tumorigenesis in Eker rats and Tsc2-/-teratomas. The present study suggests that ESCs derived from Eker rats constitute a novel experimental tool with which to analyze differentiation defects and cell-type specific pathogenesis associated with Tsc2 deficiency.
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