Inhibition of TGF-/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects. Academic Article uri icon


  • 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 (TGF-) 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- 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- receptor. BAMBI transduction significantly inhibited TGF-/Smad signaling and expression of CAF markers in human BM-MSCs treated with TGF-1 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- signaling is essential for differentiation of human BM-MSCs to CAFs in tumor microenvironments and the consequent protumor effects, and inhibiting TGF-/Smad pathway may improve the safety of MSC-based therapies in cancer patients.

published proceedings

  • Stem Cells

altmetric score

  • 0.5

author list (cited authors)

  • Shangguan, L., Ti, X., Krause, U., Hai, B. o., Zhao, Y., Yang, Z., & Liu, F.

citation count

  • 105

complete list of authors

  • Shangguan, Lei||Ti, Xinyu||Krause, Ulf||Hai, Bo||Zhao, Yanqiu||Yang, Zhenhua||Liu, Fei

publication date

  • December 2012