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

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

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1
Texas A&M Health Science Center, College of Medicine, Institute for Regenerative Medicine at Scott & White, Temple, TX 76502, USA. rlee@medicine.tamhsc.edu

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.

PMID:
23142520
DOI:
10.1016/j.stem.2012.10.001
[Indexed for MEDLINE]
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