Loss of TGf-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks

Nikki Cheng, Neil A. Bhowmick, Anna Chytil, Agnieszka E. Gorksa, Kimberly A. Brown, Rebecca Muraoka, Carlos L. Arteaga, Eric G. Neilson, Simon W. Hayward, Harold L. Moses

Research output: Contribution to journalArticle

213 Scopus citations

Abstract

Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-/β signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-β type II receptor gene in mouse mammary fibroblasts (Tgfbr2fspKO). Tgfbr2fspKO mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2fspKO mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2fspKO fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-α signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-β signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-α, MSP, and HGF signaling pathways.

Original languageEnglish (US)
Pages (from-to)5053-5068
Number of pages16
JournalOncogene
Volume24
Issue number32
DOIs
StatePublished - Jul 28 2005

Keywords

  • Mammary gland
  • Subrenal grafting
  • TGF-β
  • TGF-β receptor type II
  • Tumor progression
  • Tumor-stromal interactions

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Cheng, N., Bhowmick, N. A., Chytil, A., Gorksa, A. E., Brown, K. A., Muraoka, R., Arteaga, C. L., Neilson, E. G., Hayward, S. W., & Moses, H. L. (2005). Loss of TGf-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene, 24(32), 5053-5068. https://doi.org/10.1038/sj.onc.1208685