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

Yang, F.; Strand, D. W.; Rowley, D. R.
January 2008
Oncogene;1/17/2008, Vol. 27 Issue 4, p450
Academic Journal
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.Oncogene (2008) 27, 450–459; doi:10.1038/sj.onc.1210663; published online 16 July 2007


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