title: Inducible expression of TGFβ, snail and Zeb1 recapitulates EMT in vitro and in vivo in a NSCLC model.
abstract: 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.
authors.affiliation: Departments of Translational Research, Biochemical and Cellular Pharmacology and In Vivo Pharmacology, OSI Pharmaceuticals, Inc., Farmingdale, NY 11735, USA. gargast@osip.com
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Argast
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Krueger
authors.forename: Stuart
authors.initials: S
authors.lastname: Thomson
authors.forename: Isabela
authors.initials: I
authors.lastname: Sujka-Kwok
authors.forename: Krista
authors.initials: K
authors.lastname: Carey
authors.forename: Stacia
authors.initials: S
authors.lastname: Silva
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Connor
authors.forename: Peter
authors.initials: P
authors.lastname: Mercado
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Mulford
authors.forename: G David
authors.initials: GD
authors.lastname: Young
authors.forename: Regina
authors.initials: R
authors.lastname: Sennello
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.forename: Julie L C
authors.initials: JL
authors.lastname: Kan
authors.forename: John
authors.initials: J
authors.lastname: Haley
authors.forename: Maryland
authors.initials: M
authors.lastname: Rosenfeld-Franklin
authors.forename: David M
authors.initials: DM
authors.lastname: Epstein
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019076:Transgenes; D014183:Transplantation, Heterologous; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1