TGF-β1 induced EMT

Epithelial to mesenchymal transition (EMT) is a process by which cells of an epithelial phenotype dedifferentiate to a motile mesenchymal phenotype. The Epithelial cell reorganizes its actin cytoskeleton from a cortical junctional associated arrangement to form motile stress fibres, redistributes and down regulates its cell-cell contacts, loses its polarity, and upregulates mesenchymal markers such as α-smooth muscle actin (α-SMA) and vimentin [1]. The cell also shifts its association with the basal lamina by altering the composition of its extracellular matrix (ECM) contacts and secreting matrix metalloproteinases [2]. EMT has a role during development [3], chronic fibrotic disorders [4], and a postulated role in epithelial cancer metastasis [5].

Transforming growth factor beta-1 (TGF-β1) can trigger an EMT in cancer cells leading to metastasis [5]. In order for an adenocarcinoma cell to metastasize and relocate to a different site, it must somehow lose contact with its surrounding cells, become motile and acquire the ability to manipulate the basal lamina in order to intravasate into local blood vessels or lymph system. An EMT triggered by TGF-β1 provides a hypothetical mechanism for this occurrence. It is considered important that cancerous cells lose sensitivity to the growth inhibitory effect of TGF-β1 before they undergo EMT in vivo [5]. However loss of growth inhibition is not necessarily correlated with EMT in vitro [6].

Although the phenotypic characteristics of EMT are fairly well defined, the signalling pathways responsible for TGF-β1 induced EMT are not. The mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) have all been implicated despite no known direct link between TGF-β receptors and MAPK pathways [7,8,9]. In addition several other pathways have been implicated including Notch signalling (which is modulated by TGF-β signalling), β-catenin signalling, and Akt signalling [10,11,12]. A critical step in understanding both EMT and TGF-β signalling will be deciphering how these pathways are activated in response to TGF-β.

Refs

  1. Savagner, P. 2001. Leaving the neighborhood: molecular mechanisms involved during Epithelial-Mesenchymal Transition. BioEssays. 23: 912-923.
  2. LaGamba, D. Nawshad, A. and Hay, E.D. 2005. Microarray analysis of gene expression during Epithelial-Mesenchymal Transformation. Dev Dyn. 234: 132-42
  3. Hay, E.D. 1995. An overview of Epithelio-Mesenchymal Transformation. Acta Anat (Basel). 154: 8-20.
  4. Kalluri, R. and Neilson, E.G. 2003. Epithelial-Mesenchymal Transition and its implications for fibrosis. J Clin Invest. 112: 1776-84.
  5. Thiery, J.P. 2002. Epithelial-Mesenchymal Transitions in tumour progression. Nat Rev Cancer. 2: 442–454.
  6. Brown, K.A. Aakre, M.E. Gorska, A.E. Price, J.O. Eltom, S.E. Pietenpol, J.A. and Moses, H.L. 2004. Induction by Transforming Growth Factor-β1 of Epithelial to Mesenchymal Transition is a rare event in vitro. Breast Cancer Res. 6: R215-R231
  7. Xie, L. Law, B.K. Chytil, A.M. Brown, K.A. Aakre, M.E. Moses, H.L. 2004. Activation of the Erk pathway is required for TGF-β1–induced EMT in vitro. Neoplasia. 6: 603-610
  8. Bakin, A.V. Rinehart, C. Tomlinson, A.K. Arteaga, C.L. 2002. p38 Mitogen-Activated Protein Kinase is required for TGF-β-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci. 115: 3193-3206.
  9. Engel, M.E. McDonnell, M.A. Law, B.K. and Moses, H.L. 1999. Interdependent SMAD and JNK signaling in Transforming Growth Factor-β-mediated transcription. J Biol Chem. 274: 37413-37420.
  10. Zavadil, J. Cermak, L. Soto-Nieves, N. Böttinger, E.P. 2004. Integration of TGF-β/Smad and Jagged1/Notch signalling in Epithelial-to-Mesenchymal Transition. EMBO J. 23: 1155-1165.
  11. Kim, K. Lu, Z. and Hay, E.D. 2002. Direct evidence for a role of β-Catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int. 26: 463–476.
  12. Bakin, A.V. Tomlinson, A.K. Bhowmick, N.A. Moses, H.L. and Arteaga, C.L. 2000. Phosphatidylinositol 3-Kinase function is required for Transforming Growth Factor β -mediated Epithelial to Mesenchymal Transition and cell migration. J Biol Chem. 275: 36803-36810.
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