NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites.
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.
Division of Genetic Therapeutics, Center for Molecular Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan.
Ryosuke
R
Uchibori
Tomonori
T
Tsukahara
Hiroyuki
H
Mizuguchi
Yasushi
Y
Saga
Masashi
M
Urabe
Hiroaki
H
Mizukami
Akihiro
A
Kume
Keiya
K
Ozawa
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1