RRC ID 44115
Author Uchibori R, Tsukahara T, Mizuguchi H, Saga Y, Urabe M, Mizukami H, Kume A, Ozawa K.
Title NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites.
Journal Cancer Res
Abstract 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.
Volume 73(1)
Pages 364-72
Published 2013-1-1
DOI 10.1158/0008-5472.CAN-12-0088
PII 0008-5472.CAN-12-0088
PMID 23066037
MeSH Animals Blotting, Western Cell Adhesion / physiology Cell Line, Tumor Endothelial Cells / metabolism Flow Cytometry Humans Immunohistochemistry Male Mesenchymal Stem Cells / cytology Mesenchymal Stem Cells / metabolism* Mice Mice, Inbred BALB C NF-kappa B / metabolism* Neoplasms, Experimental / metabolism* Neoplasms, Experimental / pathology Vascular Cell Adhesion Molecule-1 / metabolism
IF 8.378
Times Cited 47
Human and Animal Cells