Journal
CELL STEM CELL
Volume 11, Issue 6, Pages 825-835Publisher
CELL PRESS
DOI: 10.1016/j.stem.2012.10.001
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Funding
- Cancer Prevention & Research Institute of Texas [RP100781]
- Temple Therapeutics, LLC
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Mesenchymal stem/stromal cells (MSCs) can either suppress or promote tumors. We found previously that incubation of human bone marrow MSCs (hMSCs) with TNF-alpha upregulated multiple genes including TRAIL, which has cancer apoptotic activity. Here, we show that weekly infusions into mice of hMSCs preactivated with TNF-alpha 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 beta-catenin and cyclin D1/D3 and an increase in p21. Thus, culturing hMSCs with TNF-alpha enhances their tumor-suppressive properties and may represent a useful strategy to develop hMSC-based approaches for the treatment of cancer.
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