Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

Oncotarget. 2015 Sep 22;6(28):25320-38. doi: 10.18632/oncotarget.4659.

Abstract

Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression.

Keywords: breast cancer; collagen I fibers; connective tissue growth factor (CTGF); epithelial-mesenchymal transition (EMT); tumor necrosis factor receptor 1 (TNFR1) pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Autocrine Communication*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Collagen Type I / metabolism*
  • Connective Tissue Growth Factor / antagonists & inhibitors
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism*
  • Disease-Free Survival
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Proteins / antagonists & inhibitors
  • I-kappa B Proteins / metabolism
  • Kaplan-Meier Estimate
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • RNA Interference
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology
  • Time Factors
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • CCN2 protein, human
  • Collagen Type I
  • I-kappa B Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • Connective Tissue Growth Factor