Mesenchymal stem cells (MSC) 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 the
tumors are presently little understood. We focused on MSC-endothelial cell (EC) adhesion following TNF-α stimulation in an attempt to elucidate these mechanisms. Interestingly, stimulation of MSCs with TNF-α enhanced the adhesion of MSCs to endothelial cells 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 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
parthenolide-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 endothelial cells. These findings have implications for the ongoing development of efficient MSC-based gene
therapies for
cancer treatment.