Bone Marrow-Derived Mesenchymal Stem Cells Provide an Advantageous Tumor Microenvironment for the Restoration of Gastric Cancer Stem Cells
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine
Abstract: In this study, we investigated the impact of UE6E7T-12 bone marrow-derived mesenchymal stem cells (BM-MSCs) on the proliferation and cluster formation of gastric carcinoma (GC)-derived MKN-7 cells. Interestingly, co-culture with UE6E7T-12 BM-MSCs increased the population of CD133+ MKN-7 cells in vitro and co-implantation of MKN-7 cells and UE6E7T-12 BM-MSCs in mice resulted in subcutaneous tumors in vivo, suggesting BM-MSCs’ function in the restoration of cancer stem cells (CSCs). By a differential analysis of gene expression profiles, we identified that co-incubation of MKN-7 cells and UE6E7T-12 BM-MSCs induced WNT5A expression in MKN-7 cells and TGF-β1 expression in UE6E7T-12 BM-MSCs, respectively. Of note, WNT5A and TGF-β1 independently enlarged the population of CD133+ MKN-7 cells, even in the absence of co-culture with UE6E7T-12 BM-MSCs. In human diffuse-type GC tissues, recruitment of CD271+ BM-MSC was detected in the tumor stroma and GC cells showed frequent positivity against WNT5A, TGF-β type I receptor and CD133. These findings suggest that BM-MSCs provide an advantageous microenvironment for cancer progression by supporting the re-acquisition and maintenance of CSCs. BM-MSC-mediated activations of the WNT and TGF-β signaling pathways may be attractive therapeutic targets for blocking the evolution of GC cells.
Key words: bone marrow-derived mesenchymal stem cells (BM-MSC), cancer stem cells, cancer-associated fibroblast (CAF), WNT5A, TGF-β