NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la signalisation NF-κB régule l'accumulation de cellules souches mésenchymateuses dans les localisations tumorales
Mesenchymal stem cells (MSCs) accumulate at tumor sites when injected into tumor-bearing mice, perhaps offering cellular vectors for cancer-targeted gene therapy. However, the molecular mechanisms involved in MSC targeting to tumors are presently little understood. We focused on MSC-endothelial cell (EC) adhesion following tumor necrosis factor-α (TNF-α) stimulation in an attempt to elucidate these mechanisms. Interestingly, stimulation of MSCs with TNF-α enhanced the adhesion of MSCs to ECs in vitro. This adhesion was partially inhibited by blocking antibodies against vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4). It is well known that TNF-α induces VCAM-1 expression via the NF-κB signaling pathway. Parthenolide (PTL) has an anti-inflammatory activity and suppressed NF-κB activity by inhibition of IκBα phosphorylation after TNF-α stimulation, and strongly inhibited TNF-α-induced VCAM-1 expression on MSCs. In vivo imaging using luciferase-expressing MSCs revealed that the bioluminescent signal gradually increased at tumor sites in mice injected with untreated MSCs. In contrast, we observed very weak signals at tumor sites in mice injected with PTL-treated MSCs. Our results suggest that NF-κB activity regulates MSC accumulation at tumors, by inducing VCAM-1 and thereby its interaction with tumor vessel ECs. These findings have implications for the ongoing development of efficient MSC-based gene therapies for cancer treatment.