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

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