title: Inhibition of TGF-β/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects.
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.
authors.affiliation: Institute for Regenerative Medicine at Scott & White, Molecular and Cellular Medicine Department, Texas A&M Health Science Center, Temple, Texas, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shangguan
authors.forename: Xinyu
authors.initials: X
authors.lastname: Ti
authors.forename: Ulf
authors.initials: U
authors.lastname: Krause
authors.forename: Bo
authors.initials: B
authors.lastname: Hai
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Yang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction; D051785:Smad Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C485672:Bambi protein, mouse; D008565:Membrane Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta