Inducible expression of TGFβ, Snail and Zeb1 recapitulates EMT in vitro and in vivo in a NSCLC model
| Autor: | Julie L.C. Kan, Stuart Thomson, David Epstein, Joseph S. Krueger, Maryland Rosenfeld-Franklin, Regina Sennello, John D. Haley, G. David Young, Peter Mercado, Jonathan A. Pachter, Krista Carey, Matthew O'Connor, Robert A. Wild, Stacia Silva, Gretchen M. Argast, Iain J. Mulford, Isabela Sujka-Kwok |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Epithelial-Mesenchymal Transition Stromal cell Transplantation Heterologous Mice SCID Biology Mice Downregulation and upregulation Transforming Growth Factor beta In vivo Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Animals Humans Transgenes Epithelial–mesenchymal transition Autocrine signalling Cell Proliferation Homeodomain Proteins Mesenchymal stem cell Zinc Finger E-box-Binding Homeobox 1 General Medicine Gene Expression Regulation Neoplastic Transplantation Disease Models Animal Phenotype Oncology embryonic structures Cancer research Female Snail Family Transcription Factors Neoplasm Transplantation Transcription Factors Transforming growth factor |
| Zdroj: | Clinical & Experimental Metastasis. 28:593-614 |
| ISSN: | 1573-7276 0262-0898 |
| DOI: | 10.1007/s10585-011-9394-8 |
| Popis: | The progression of cancer from non-metastatic to metastatic is the critical transition in the course of the disease. The epithelial to mesenchymal transition (EMT) is a mechanism by which tumor cells acquire characteristics that improve metastatic efficiency. Targeting EMT processes in patients is therefore a potential strategy to block the transition to metastatic cancer and improve patient outcome. To develop models of EMT applicable to in vitro and in vivo settings, we engineered NCI-H358 non-small cell lung carcinoma cells to inducibly express three well-established drivers of EMT: activated transforming growth factor β (aTGFβ), Snail or Zeb1. We characterized the morphological, molecular and phenotypic changes induced by each of the drivers and compared the different end-states of EMT between the models. Both in vitro and in vivo, induction of the transgenes Snail and Zeb1 resulted in downregulation of epithelial markers and upregulation of mesenchymal markers, and reduced the ability of the cells to proliferate. Induced autocrine expression of aTGFβ caused marker and phenotypic changes consistent with EMT, a modest effect on growth rate, and a shift to a more invasive phenotype. In vivo, this manifested as tumor cell infiltration of the surrounding mouse stromal tissue. Overall, Snail and Zeb1 were sufficient to induce EMT in the cells, but aTGFβ induced a more complex EMT, in which changes in extracellular matrix remodeling components were pronounced. |
| Databáze: | OpenAIRE |
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