title: The relevance of the TGF-β Paradox to EMT-MET programs.
abstract: The role of transforming growth factor-β (TGF-β) during tumorigenesis is complex and paradoxical, reflecting its ability to function as a tumor suppressor in normal and early-stage cancers, and as a tumor promoter in their late-stage counterparts. The switch in TGF-β function is known as the "TGF-β Paradox," whose manifestations are intimately linked to the initiation of epithelial-mesenchymal transition (EMT) programs in developing and progressing carcinomas. Indeed, as carcinoma cells emerge from EMT programs stimulated by TGF-β, they readily display a variety of acquired phenotypes that provide a selective advantage to growing carcinomas, including (i) enhanced cell migration and invasion; (ii) heightened resistance to cytotoxic agents, targeted chemotherapeutic, and radiation treatments; and (iv) boosted expansion of cancer-initiating and stem-like cell populations that underlie tumor metastasis and disease recurrence. At present, the molecular, cellular, and microenvironmental mechanisms that enable post-EMT and metastatic carcinoma cells to hijack the oncogenic activities of TGF-β remain incompletely understood. Additionally, the molecular mechanisms that counter EMT programs and limit the aggressiveness of late-stage carcinomas, events that transpire via mesenchymal-epithelial transition (MET) reactions, also need to be further elucidated. Here we review recent advances that provide new insights into how TGF-β promotes EMT programs in late-stage carcinoma cells, as well as how these events are balanced by MET programs during the development and metastatic progression of human carcinomas.
authors.affiliation: Case Comprehensive Cancer Center, Division of General Medical Sciences-Oncology, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road Cleveland, OH 44106, United States.
authors.forename: Chevaun D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Jenny G
authors.initials: JG
authors.lastname: Parvani
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C491738:ERP29 protein, human; C470830:GRHL2 protein, human; D006360:Heat-Shock Proteins; D016023:Integrins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl
keywords: Epithelial plasticity; Metastasis; TGF-β