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Cell Tissue Res. 2012 Jan;347(1):85-101. doi: 10.1007/s00441-011-1199-1. Epub 2011 Jun 21.

Deconstructing the mechanisms and consequences of TGF-β-induced EMT during cancer progression.

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  • 1Case Comprehensive Cancer Center, Division of General Medical Sciences-Oncology, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA.

Abstract

Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that regulates mammalian development, differentiation, and homeostasis in essentially all cell types and tissues. TGF-β normally exerts anticancer activities by prohibiting cell proliferation and by creating cell microenvironments that inhibit cell motility, invasion, and metastasis. However, accumulating evidence indicates that the process of tumorigenesis, particularly that associated with metastatic progression, confers TGF-β with oncogenic activities, a functional switch known as the "TGF-β paradox." The molecular determinants governing the TGF-β paradox are complex and represent an intense area of investigation by researchers in academic and industrial settings. Recent findings link genetic and epigenetic events in mediating the acquisition of oncogenic activity by TGF-β, as do aberrant alterations within tumor microenvironments. These events coalesce to enable TGF-β to direct metastatic progression via the stimulation of epithelial-mesenchymal transition (EMT), which permits carcinoma cells to abandon polarized epithelial phenotypes in favor of apolar mesenchymal-like phenotypes. Attempts to deconstruct the EMT process induced by TGF-β have identified numerous signaling molecules, transcription factors, and microRNAs operant in mediating the initiation and resolution of this complex transdifferentiation event. In addition to its ability to enhance carcinoma cell invasion and metastasis, EMT also endows transitioned cells with stem-like properties, including the acquisition of self-renewal and tumor-initiating capabilities coupled to chemoresistance. Here, we review recent findings that delineate the pathophysiological mechanisms whereby EMT stimulated by TGF-β promotes metastatic progression and disease recurrence in human carcinomas.

PMID:
21691718
[PubMed - indexed for MEDLINE]
PMCID:
PMC3723118
Free PMC Article

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