ABSTRACT
BACKGROUND: Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. METHODS: To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. RESULTS: Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. CONCLUSION: Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. KEY POINTS: 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment.2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.
Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Mesenchymal Stem Cells , Cell Line, Tumor , Complement C5a/genetics , Humans , Neoplasm Invasiveness , Tumor Microenvironment , Zinc Finger E-box-Binding Homeobox 1/genetics , p38 Mitogen-Activated Protein Kinases/geneticsABSTRACT
Background: Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods: Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results: GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion: The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.
Subject(s)
Brain Neoplasms/drug therapy , Deoxyglucose/pharmacology , Glioblastoma/drug therapy , Metformin/pharmacology , Animals , Antimetabolites/pharmacology , Apoptosis/drug effects , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Drug Synergism , Drug Therapy, Combination , Energy Metabolism/drug effects , Glioblastoma/metabolism , Glioblastoma/pathology , Glycolysis/drug effects , Humans , Hypoglycemic Agents/pharmacology , Mice , Mice, Nude , Oxidative Phosphorylation/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Ionic hydrogel-based ion concentration polarization devices have been demonstrated as platforms to study nanoscale ion transport and to develop engineering applications, such as protein preconcentration and ionic diodes/transistors. Using a microfluidic system composed of a perm-selective hydrogel, we demonstrated a micro/nanofluidic device for the preconcentration of biological samples using a new class of ion concentration polarization mechanism called "capillarity ion concentration polarization" (CICP). Instead of an external electrical voltage source, the capillary force of the perm-selective hydrogel spontaneously generated an ion depletion zone in a microfluidic channel by selectively absorbing counter-ions in a sample solution. We demonstrated a reasonable preconcentration factor (â¼100-fold/min) using the CICP device. Although the efficiency was lower than that of conventional electrokinetic ICP operation due to the absence of a drift ion migration, this mechanism was free from the undesirable instability caused by a local amplified electric field inside the ion depletion zone so that the mechanism should be suitable especially for an application where the contents were electrically sensitive. Therefore, this simple system would provide a point-of-care diagnostic device for which the sample volume is limited and a simplified sample handling is demanded.
