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

Oncogene volume 27, pages 450–459 (2008)Cite this article

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.

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Acknowledgements

We thank Drs Neil Bhowmick and Harold Moses for providing prostate tissue from a Tgfbr2floxE2/floxE2 mouse, Drs Daniel Silver and David Livingston for providing HR-MMPCreGFP and HR-MMPCreGFPY324F vectors, Drs Lisa Choy Tomlinson and Rik Derynck for providing pLPCX-N-Flag-Smad3ΔSSVS and pLPCX vectors, Dr Gary Nolan for providing the pBMN-LacZ and pBMN-I-eGFP vectors, and Dr Walter Nickel for providing the pRev-TRE2-FGF2-GFP vector. We thank Dr Sem Phan for providing the α-SMAp-luc vector, Drs. Zendra Zehner and Susan Rittling for the –757Cat vector, Dr David Loskutoff for the p800Luc vector, and Drs. Sylviane Dennler and Stephanie Huet for the (CAGA)12MLP vector. We also thank Liz Hopkins for histological preparation of tissue, Truong Dang for maintenance of cell cultures, and Dr Xin-hua Feng, Dr Lisa Choy Tomlinson, Dr Steven Ressler and Isaiah Schauer for helpful discussions. This work was supported by NIH grants, RO1-CA058093, RO1-DK045909, SPORE P50-CA58204, UO1-CA84296, U54-CA126568 and Department of Defense grants W81XWH-04-1-0189, W81XWH-07-1-0200.

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  1. F Yang and D W Strand: These authors have contributed equally to this work.

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  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    F Yang, D W Strand & D R Rowley

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  1. F Yang
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Correspondence to D R Rowley.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Yang, F., Strand, D. & Rowley, D. Fibroblast growth factor-2 mediates transforming growth factor-β action in prostate cancer reactive stroma. Oncogene 27, 450–459 (2008). https://doi.org/10.1038/sj.onc.1210663

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