Inhibition of TGF-β/Smad Signaling by BAMBI Blocks Differentiation of Human Mesenchymal Stem Cells to Carcinoma-Associated Fibroblasts and Abolishes their Protumor Effects§

Authors

  • Lei Shangguan,

    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
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  • Xinyu Ti,

    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
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  • Ulf Krause,

    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
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  • Bo Hai,

    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
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  • Yanqiu Zhao,

    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
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  • Zhenhua Yang,

    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
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  • Fei Liu

    Corresponding author
    1. Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA
    • 5701 Airport Rd., Module C, Temple, Texas 76502, USA
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    • Telephone: +1-254-771-6813; Fax: +1-254-771-6839


  • Author contributions: F.L.: conceived and supervised the study; L.S. and X.T.: performed most of the experiments; U.K.: contributed with FACS analysis; B.H., Y.Z., and Z.Y.: contributed with vector construction and cell culture; F.L.: wrote the manuscript. L.S. and X.T. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 7, 2012.

Abstract

Bone marrow mesenchymal stem cells (BM-MSCs) have multiple therapeutic potentials for regenerative, anti-inflammatory, and immunomodulatory purposes and also show promise as vehicles for gene therapy of various metastatic cancers based on their tumor-tropic capacity. However, BM-MSCs are also a source of carcinoma-associated fibroblasts (CAFs) and may promote growth and metastasis of cancer. Transforming growth factor β (TGF-β) signaling is required to induce CAF differentiation of mouse BM-MSCs in vivo and can induce expression of some CAF markers in human BM-MSCs in vitro. To determine whether inhibiting TGF-β signaling in human BM-MSCs can block their differentiation to CAFs induced by tumor microenvironments and the consequent protumor effects, we transduced human BM-MSCs with a lentiviral vector encoding bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a decoy TGF-β receptor. BAMBI transduction significantly inhibited TGF-β/Smad signaling and expression of CAF markers in human BM-MSCs treated with TGF-β1 or tumor-conditioned medium or cocultured with cancer cells, but did not alter the stem cell properties and the tumor-tropic property of MSCs. In addition, BAMBI transduction disrupted the cytokine network mediating the interaction between MSCs and breast cancer cells. Consequently, BAMBI transduction abolished protumor effects of BM-MSCs in vitro and in an orthotopic breast cancer xenograft model, and instead significantly inhibited growth and metastasis of coinoculated cancer. These results indicated that TGF-β signaling is essential for differentiation of human BM-MSCs to CAFs in tumor microenvironments and the consequent protumor effects, and inhibiting TGF-β/Smad pathway may improve the safety of MSC-based therapies in cancer patients. STEM CELLS 2012;30:2810–2819

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