Dataset Information

EMT tumorigenesis in the mouse mammary gland.

ABSTRACT: The term EMT (epithelial-mesenchymal transition) is used in many settings. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors. In mice, most 'EMT' tumors have a spindle cell phenotype. The definition of EMT is controversial because spindle cell tumors are not common in humans, especially in human breast cancers. Spindle cell tumors of the mouse mammary gland have been observed for many years where they are usually classified as sarcomas or carcinosarcomas. Genetically engineered mice develop mammary spindle cell tumors that appear to arise in the epithelium and undergo EMT. To better understand the origin and evolution of these spindle cell tumors in progression and metastases, seven cohorts of spindle cell tumors from the archives of the University of California, Davis Mutant Mouse Pathology Laboratory were studied. This study provides experimental and immunohistochemical evidence of EMT showing that dual epithelial and mesenchymal staining of tumor spindle cells identifies some, but not all, EMT-type tumors in the mouse. This suggests that potential EMT tumors are best designated EMT-phenotype tumors.

SUBMITTER: Damonte P

PROVIDER: S-EPMC2754828 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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EMT tumorigenesis in the mouse mammary gland.

Damonte Patrizia P Gregg Jeffrey P JP Borowsky Alexander D AD Keister Blaine A BA Cardiff Robert D RD

Laboratory investigation; a journal of technical methods and pathology 20071008 12

The term EMT (epithelial-mesenchymal transition) is used in many settings. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a specific diagnostic category of tumors. In mice, most 'EMT' tumors have a spindle cell phenotype. The definition of EMT is controversial because spind ...[more]

PMID: 17922020

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Project description:Retrotransposons copy their sequences via an RNA intermediate, followed by reverse transcription into cDNA and random insertion, into a new genomic locus. New retrotransposon copies may lead to cell transformation and/or tumorigenesis through insertional mutagenesis. Methylation is a major defense mechanism against retrotransposon RNA expression and retrotransposition in differentiated cells, whereas stem cells are relatively hypo?methylated. Epithelial?to?mesenchymal transition (EMT), which transforms normal epithelial cells into mesenchymal?like cells, also contributes to tumor progression and tumor metastasis. Cancer stem cells (CSCs), a fraction of undifferentiated tumor?initiating cancer cells, are reciprocally related to EMT. In the present study, the outcome of long terminal repeat (LTR)?Viral?Like 30 (VL30) retrotransposition was examined in mouse mammary stem?like/progenitor HC11 epithelial cells. The transfection of HC11 cells with a VL30 retrotransposon, engineered with an EGFP?based retrotransposition cassette, elicited a higher retrotransposition frequency in comparison to differentiated J3B1A and C127 mouse mammary cells. Fluorescence microscopy and PCR analysis confirmed the specificity of retrotransposition events. The differentiated retrotransposition?positive cells retained their epithelial morphology, while the respective HC11 cells acquired mesenchymal features associated with the loss of E?cadherin, the induction of N?cadherin, and fibronectin and vimentin protein expression, as well as an increased transforming growth factor (TGF)??1, Slug, Snail?1 and Twist mRNA expression. In addition, they were characterized by cell proliferation in low serum, and the acquisition of CSC?like properties indicated by mammosphere formation under anchorage?independent conditions. Mammospheres exhibited an increased Nanog and Oct4 mRNA expression and a CD44+/CD24?/low antigenic phenotype, as well as self?renewal and differentiation capacity, forming mammary acini?like structures. DNA sequencing analysis of retrotransposition?positive HC11 cells revealed retrotransposed VL30 copies integrated at the vicinity of EMT?, cancer type? and breast cancer?related genes. The inoculation of these cells into Balb/c mice produced cytokeratin?positive tumors containing pancytokeratin?positive cells, indicative of cell invasion features. On the whole, the findings of the present study demonstrate, for the first time, to the best of our knowledge, that stem?like epithelial HC11 cells are amenable to VL30 retrotransposition associated with the induction of EMT and CSC generation, leading to tumorigenesis.

Dataset Information

EMT tumorigenesis in the mouse mammary gland.

Publications

EMT tumorigenesis in the mouse mammary gland.

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