Preactivation of human MSCs with TNF-α enhances tumor-suppressive activity

Cell Stem Cell. 2012 Dec 7;11(6):825-35. doi: 10.1016/j.stem.2012.10.001. Epub 2012 Nov 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemokines
  • Coculture Techniques
  • Doxorubicin / pharmacology
  • Humans
  • Infusions, Intravenous
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / pathology*
  • Mice
  • Mice, SCID
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Xenograft Model Antitumor Assays


  • Adaptor Proteins, Signal Transducing
  • Chemokines
  • DKK3 protein, human
  • Intercellular Signaling Peptides and Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha
  • Doxorubicin