Preactivation of Human MSCs with TNF-± Enhances Tumor-Suppressive Activity
Menée in vitro et à l'aide d'un modèle murin, cette étude montre que la mise en culture de cellules souches mésenchymateuses avec du TNF-
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 ²-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. º Mesenchymal stem cells (MSCs) exposed to TNF-
α
activate TRAIL and DKK3 expression º Activated MSCs decrease tumors in mice caused by a human breast cancer cell line º Activated MSCs also induce apoptosis in several different cancer cell lines in culture º TRAIL from MSCs causes apoptosis and DKK3 decreases cell cycling of cancer cells Activating human MSCs with TNF-
α
upregulates TRAIL and DKK3 and enhances their ability to induce apoptosis in a broad range of cancer cells in vitro and inhibit tumor growth in vivo.
http://linkinghub.elsevier.com/retrieve/pii/S1934590912005814