Fibroblast growth factor-2 mediates transforming growth factor-Β action in prostate cancer reactive stroma

F. Yang, D. W. Strand, D. R. Rowley

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) is overexpressed at sites of wound repair and in most adenocarcinomas including prostate cancer. In stromal tissues, TGF-β regulates cell proliferation, phenotype and matrix synthesis. To address mechanisms of TGF-β action in cancer-associated reactive stroma, we developed prostate stromal cells null for TGF-β receptor II (TβRII) or engineered to express a dominant-negative Smad3 to attenuate TGF-β signaling. The differential reactive stroma (DRS) xenograft model was used to evaluate altered stromal TGF-β signaling on LNCaP tumor progression. LNCaP xenograft tumors constructed with TβRII null or dominant-negative Smad3 stromal cells exhibited a significant reduction in mass and microvessel density relative to controls. Additionally, decreased cellular fibroblast growth factor-2 (FGF-2) immunostaining was associated with attenuated TGF-β signaling in stroma. In vitro, TGF-β stimulated stromal FGF-2 expression and release. However, stromal cells with attenuated TGF-β signaling were refractory to TGF-β-stimulated FGF-2 expression and release. Re-expression of FGF-2 in these stromal cells in DRS xenografts resulted in restored tumor mass and microvessel density. In summary, these data show that TGF-β signaling in reactive stroma is angiogenic and tumor promoting and that this effect is mediated in part through a TβRII/Smad3-dependent upregulation of FGF-2 expression and release.

Original languageEnglish (US)
Pages (from-to)450-459
Number of pages10
JournalOncogene
Volume27
Issue number4
DOIs
StatePublished - Jan 17 2008

Keywords

  • Angiogenesis
  • Fibroblast growth factor
  • Prostate cancer
  • Stroma
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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