The Study of Glioma-derived Exosomes in Tumor Progression via MCT1 and Its Ancillary Protein, CD147

Malignant glioma is one of the most fatal tumors occurring in the central nervous system (CNS). Despite its common origin in glia and glial stem cells, diverse subtypes of glioma cells (GMs) are generated with various oncogenic mutations. Major types of gliomas include astrocytomas, oligodendrogliomas, and glioblastoma multiform (GBM). Irrespective of the type of glioma, one of the hallmarks of glioma progression is the metabolic shift towards aerobic glycolysis with the enhancement of glycolytic enzymes and transporters, including monocarboxylate transporter 1 (MCT1) and its binding protein CD147, facilitating the movement of lactate across the plasma membrane. Exosomes, cell-secreted vesicles that range from 30-150 nm in size, exert multiple critical biological functions on the intercellular communication and modulation of the tumor microenvironment. Interestingly, GMs in the hypoxic microenvironment secrete tremendous amounts of exosomes, which can spread to distant target cells as well as surrounding stromal cells (SMs). However, the effects of GMs-derived exosomes on glioma progression have not been holistically investigated, particularly through the regulation of the release and uptake of exosomes as well as the production of pro-oncogenic exosomes by metabolic alterations.Our preliminary data revealed that hypoxia-induced exosomes contained significant levels of MCT1 and CD147 which could be detected by sensitive biosensing techniques, including Local Surface Plasmon Resonance (LSPR) and Atomic Force Microscopy (AFM). Importantly, we first found that the level of MCT1 and CD147 in the membrane of GMs-derived exosomes reflected the metabolic and phenotypic status of parental GMs, suggesting that exosomal MCT1 and CD147 are great biomarkers for the detection of glioma progression in a liquid biopsy.In further experiments, we found that hypoxia induced GMs-derived and endothelial cell (ECs)-derived exosomes could enter recipient cells, altering their metabolism and phenotype, which was blocked partly by inhibiting the activity of MCT1 and CD147 at the cellular and exosomal level. Thus, we hypothesize that the exosome-mediated interactions between GMs and ECs are important processes for glioma progression, which can be regulated partly by MCT1 and CD147 at the level of cells and exosomes. Therefore, we plan on conducting experiments to determine the effect of loss or gain of MCT1 or CD147 function in the exosome-mediated interactions between GMs and ECs under hypoxia. Eventually, we hope to determine whether the inhibitors for MCT1 or CD147 together with an anti-glioma agent, temozolomide (TMZ), could reduce glioma progression partly by controlling the exosome-mediated phenotypic change of GMs and ECs under hypoxia.