title: Preactivation of human MSCs with TNF-α enhances tumor-suppressive activity.
abstract: Mesenchymal stem/stromal cells (MSCs) can either suppress or promote tumors. We found previously that incubation of human bone marrow MSCs (hMSCs) with TNF-α upregulated multiple genes including TRAIL, which has cancer apoptotic activity. Here, we show that weekly infusions into mice of hMSCs preactivated with TNF-α inhibited the progression of lung tumors formed from MDA-MB-231 breast cancer cells (MDA). In coculture, preactivated hMSCs induced apoptosis in MDA and several other TRAIL-sensitive cancer cell lines. TRAIL was further upregulated by apoptotic MDA cells in a TLR3-dependent manner; this feedforward cycle increased MDA cell apoptosis, and the chemotherapeutic drug doxorubicin had a synergistic effect. Also, activated hMSCs secreted DKK3 to suppress MDA cell cycling, leading to a decrease in β-catenin and cyclin D1/D3 and an increase in p21. Thus, culturing hMSCs with TNF-α enhances their tumor-suppressive properties and may represent a useful strategy to develop hMSC-based approaches for the treatment of cancer.
authors.affiliation: Texas A&M Health Science Center, College of Medicine, Institute for Regenerative Medicine at Scott & White, Temple, TX 76502, USA. rlee@medicine.tamhsc.edu
authors.forename: Ryang Hwa
authors.initials: RH
authors.lastname: Lee
authors.forename: Nara
authors.initials: N
authors.lastname: Yoon
authors.forename: John C
authors.initials: JC
authors.lastname: Reneau
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines; D018920:Coculture Techniques; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin