The Study of Glioma-derived Exosomes as Biomarkers and Functional Mediators via MCT1, CD147, and CD44


Student thesis: Doctoral Thesis

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Award date26 Aug 2019


Glioma is a lethal brain tumor in the central nervous system (CNS). In various tumors, including glioma, the rate of glycolysis significantly increases even though oxygen is present, which is generally referred as Warburg effect. This results in the production of profound amount of lactates by glioma cells (GMs), demanding the augmentation of monocarboxylate transporter 1 (MCT1) and its chaperon CD147 to pump lactates out of GMs. This metabolic reprogramming has been proposed to play a crucial role in the communication between GMs and neighboring cells. Indeed, it has been found that malignant GMs release abundant quantity of exosomes which are a type of extracellular vesicles (EVs) with an approximate size of 30-200 nm, and they are a crucial shuttle vehicle to deliver various molecules, including microRNA, to cells around GMs. Interestingly, owing to their small size, they have been found to be present in the blood and cerebrospinal fluid (CSF), suggesting that they can be systemic non-invasive biomarkers for glioma.

The present study demonstrated that increased release of exosomes from hypoxic GMs was mediated by MCT1 and CD147- dependent increased intracellular calcium and, importantly, the exosomes released from hypoxic GMs contained enhanced amount of MCT1 and CD147 which were detected precisely via non-invasive localized surface plasmon resonance (LSPR) spectroscopy and atomic force microscopy (AFM) as well as various molecular and histology techniques, including immunogold electron microscopy, enzyme-linked immune sorbent assay (ELISA), western blot, and immunocytochemistry, which provided further information of parent GMs’ metabolism, suggesting that exosomal MCT1 and CD147 could be potential biomarkers for glioma progression associated with metabolic adaptation. In addition, the close correlation was observed between level of exosomal-MCT1 and CD147 and their change of biophysical properties, which was demonstrated through measuring zeta potential, roughness, stiffness, and adhesion force, suggesting the significance of biophysical properties of GMs-derived exosomes as additional biomarkers for glioma progression.

In the further study, cell surface protein CD44, playing an important role in the migration and invasion of GMs, was also identified in GMs-derived exosomes. Using a novel titanium nanostructure based LSPR biosensor, exosomal CD44 was quantitatively detected to monitor GMs’ migration. Additionally, using the biotinylated antibody‐functionalized TiN (BAF‐TiN) LSPR biosensor, epidermal growth factor receptor variant‐III (EGFRvIII) mutant protein of GMs-derived exosomes was sensitively and selectively detected for the first time, demonstrating the significance of label‐free biosensing of exosomal tumor specific proteins as liquid biopsy.

In the study of roles of GMs-derived exosomes in tumor progression, the effect of loss and gain of MCT1 and CD147 functions, and loss of CD44 functions in endothelial cells and GMs has been investigated. MCT1-, CD147-, or CD44- enhanced exosomes promoted endothelial cells tube formation as well as GMs malignancy, suggesting the crucial role of GMs-derived exosomes in glioma progression.

Finally, exosomes has been developed as drug delivery vehicle for glioma because they can be delivered to the brain. A microfluidic device has been developed by using soft lithography for loading drug into the exosomes in the presence of saponin, which is a membrane permeabilizing agent. This microfluidic device augmented the loading efficiency of doxorubicin into the exosomes, supporting its usefulness to study the exosome-mediated drug delivery for glioma treatment.

    Research areas

  • Glioma, Metabolism, Exosome, MCT1, CD147, CD44, EGFRvIII, Biosensing, LSPR, AFM, Drug Delivery