title: TGFβ and matrix-regulated epithelial to mesenchymal transition.
abstract: BACKGROUND
  The progression of cancer through stages that guide a benign hyperplastic epithelial tissue towards a fully malignant and metastatic carcinoma, is driven by genetic and microenvironmental factors that remodel the tissue architecture. The concept of epithelial-mesenchymal transition (EMT) has evolved to emphasize the importance of plastic changes in tissue architecture, and the cross-communication of tumor cells with various cells in the stroma and with specific molecules in the extracellular matrix (ECM).
  
  
  OBJECTIVE
  Among the multitude of ECM-embedded cytokines and the regulatory potential of ECM molecules, this article focuses on the cytokine transforming growth factor β (TGFβ) and the glycosaminoglycan hyaluronan, and their roles in cancer biology and EMT. For brevity, we concentrate our effort on breast cancer.
  
  
  CONCLUSIONS
  Both normal and abnormal TGFβ signaling can be detected in carcinoma and stromal cells, and TGFβ-induced EMT requires the expression of hyaluronan synthase 2 (HAS2). Correspondingly, hyaluronan is a major constituent of tumor ECM and aberrant levels of both hyaluronan and TGFβ are thought to promote a wounding reaction to the local tissue homeostasis. The link between EMT and metastasis also involves the mesenchymal-epithelial transition (MET). ECM components, signaling networks, regulatory non-coding RNAs and epigenetic mechanisms form the network of regulation during EMT-MET.
  
  
  CONCLUSIONS
  Understanding the mechanism that controls epithelial plasticity in the mammary gland promises the development of valuable biomarkers for the prognosis of breast cancer progression and even provides new ideas for a more integrative therapeutic approach against disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden. Electronic address: aris.moustakas@imbim.uu.se.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden. Electronic address: evi.heldin@licr.uu.se.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Heldin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Epithelial–mesenchymal transition; Hyaluronan; Proteoglycan; Signal transduction; Transforming growth factor β; Tumor invasiveness