Tenascin-C Induces Phenotypic Changes in Fibroblasts to Myofibroblasts with High Contractility through the Integrin αvβ1/Transforming Growth Factor β/SMAD Signaling Axis in Human Breast Cancer.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0370502 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-2191 (Electronic) Linking ISSN: 00029440 NLM ISO Abbreviation: Am J Pathol Subsets: MEDLINE
    • Publication Information:
      Publication: 2011-: New York : Elsevier
      Original Publication: Philadelphia [etc.] American Assn. of Pathologists [etc.]
    • Subject Terms:
      Breast Neoplasms/*pathology ; Fibroblasts/*pathology ; Myofibroblasts/*pathology ; Tenascin/*pharmacology; Breast Neoplasms/metabolism ; Cell Differentiation/drug effects ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/metabolism ; Extracellular Matrix Proteins/pharmacology ; Fibroblasts/metabolism ; Humans ; Myofibroblasts/metabolism ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/pharmacology ; Phosphorylation/drug effects ; Receptors, Vitronectin/metabolism ; Signal Transduction/physiology ; Tenascin/metabolism ; Transforming Growth Factor beta/metabolism
    • Abstract:
      Tenascin-C (TNC) is strongly expressed by fibroblasts and cancer cells in breast cancer. To assess the effects of TNC on stromal formation, we examined phenotypic changes in human mammary fibroblasts treated with TNC. The addition of TNC significantly up-regulated α-smooth muscle actin (α-SMA) and calponin. TNC increased the number of α-SMA- and/or calponin-positive cells with well-developed stress fibers in immunofluorescence, which enhanced contractile ability in collagen gel contraction. The treatment with TNC also significantly up-regulated its own synthesis. Double immunofluorescence of human breast cancer tissues showed α-SMA- and/or calponin-positive myofibroblasts in the TNC-deposited stroma. Among several receptors for TNC, the protein levels of the αv and β1 integrin subunits were significantly increased after the treatment. Immunofluorescence showed the augmented colocalization of αv and β1 at focal adhesions. Immunoprecipitation using an anti-αv antibody revealed a significant increase in coprecipitated β1 with TNC in lysates. The knockdown of αv and β1 suppressed the up-regulation of α-SMA and calponin. The addition of TNC induced the phosphorylation of SMAD2/3, whereas SB-505124 and SIS3 blocked myofibroblast differentiation. Therefore, TNC enhances its own synthesis by forming a positive feedback loop and increases integrin αvβ1 heterodimer levels to activate transforming growth factor-β signaling, which is followed by a change to highly contractile myofibroblasts. TNC may essentially contribute to the stiffer stromal formation characteristic of breast cancer tissues.
      (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
    • Accession Number:
      0 (Extracellular Matrix Proteins)
      0 (Nerve Tissue Proteins)
      0 (Receptors, Vitronectin)
      0 (Tenascin)
      0 (Transforming Growth Factor beta)
      0 (integrin alphavbeta1)
      AAU3ZC4196 (neuronectin)
    • Publication Date:
      Date Created: 20200711 Date Completed: 20201118 Latest Revision: 20201118
    • Publication Date:
      20231215
    • Accession Number:
      10.1016/j.ajpath.2020.06.008
    • Accession Number:
      32650003