Small extracellular vesicles promote invadopodia activity in glioblastoma cells in a therapy-dependent manner (original) (raw)
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Breaking through the glioblastoma micro-environment via extracellular vesicles
Oncogene, 2020
Glioblastoma (GBM) is the most common and most aggressive brain tumour. Prognosis remains poor, despite the combined treatment of radio- and chemotherapy following surgical removal. GBM cells coexist with normal non-neoplastic cells, including endothelial cells, astrocytes and immune cells, constituting a complex and dynamic tumour micro-environment (TME). Extracellular vesicles (EVs) provide a critical means of bidirectional inter-cellular communication in the TME. Through delivery of a diverse range of genomic, lipidomic and proteomic cargo to neighbouring and distant cells, EVs can alter the phenotype and function of the recipient cell. As such, EVs have demonstrated their role in promoting angiogenesis, immune suppression, invasion, migration, drug resistance and GBM recurrence. Moreover, EVs can reflect the phenotype of the cells within the TME. Thus, in conjunction with their accessibility in biofluids, they can potentially serve as a biomarker reservoir for patient prognosis,...
Role of extracellular vesicles in glioma progression
Molecular aspects of medicine, 2017
The role of extracellular vesicles in cancer biology has emerged as a focus of the study of great importance and has been shown to directly influence tumour development in several cancers including brain tumours, such as gliomas. Gliomas are the most aggressive brain tumours, and in the last time, a considerable effort has been made to understand their biology. Studies focus in the signalling pathways involved in the processes of angiogenesis, viability, drug resistance and immune response evasion, as well as gliomas ability to infiltrate healthy tissue, a phenomenon regulated by the migratory and invasive capacity of the cells within a tumour. In this review, we summarize the different types and classifications of extracellular vesicles, their intravesicular content, and their role in the regulation of tumour progression processes in glioma.
International Journal of Molecular Sciences
Extracellular vesicles (EVs) are widely investigated in glioblastoma multiforme (GBM) for their involvement in regulating GBM pathobiology as well as for their use as potential biomarkers. EVs, through cell-to-cell communication, can deliver proteins, nucleic acids, and lipids that are able to reprogram tumor-associated macrophages (TAMs). This research is aimed to concentrate, characterize, and identify molecular markers of EVs subtypes released by temozolomide (TMZ)-treated and non TMZ-treated four diverse GBM cells. Morphology, size distribution, and quantity of small (sEVs) and large (lEVs) vesicles were analyzed by cryo-TEM. Quality and quantity of EVs surface markers were evaluated, having been obtained by Western blotting. GBM cells shed a large amount of EVs, showing a cell line dependent molecular profile A comparative analysis distinguished sEVs and lEVs released by temozolomide (TMZ)-treated and non TMZ-treated GBM cells on the basis of quantity, size and markers expressi...
Extracellular Vesicle-Mediated Communication between the Glioblastoma and Its Microenvironment
Cells
The glioblastoma is the most malignant form of brain cancer. Glioblastoma cells use multiple ways of communication with the tumor microenvironment in order to tune it for their own benefit. Among these, extracellular vesicles have emerged as a focus of study in the last few years. Extracellular vesicles contain soluble proteins, DNA, mRNA and non-coding RNAs with which they can modulate the phenotypes of recipient cells. In this review we summarize recent findings on the extracellular vesicles-mediated bilateral communication established between glioblastoma cells and their tumor microenvironment, and the impact of this dialogue for tumor progression and recurrence.
Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence
Annual Review of Genomics and Human Genetics
High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress.We desperately need a better biologic understanding of these complicated tumors in a complicated organ.One area of rejuvenated study relates to extracellular vesicles (EVs)—membrane-enclosed nano- or microsized particles that originate from the endosomal system or are shed from the plasma membrane. EVs contribute to tumor heterogeneity (including the maintenance of glioma stem cells or their differentiation), the impacts of hypoxia (angiogenesis and coagulopathies), interactions amid the tumor microenvironment (concerning the survival of astrocytes, neurons, endothelial cells, blood vessels, the blood–brain barrier, and the ensuing inflammation), and in...
Journal of neurosurgery, 2017
OBJECTIVE Glioblastoma is the most common primary central nervous system tumor in adults. These tumors are highly invasive and infiltrative and result in tumor recurrence as well as an extremely poor patient prognosis. The current standard of care involves surgery, radiotherapy, and chemotherapy. However, previous studies have suggested that glioblastoma cells that survive treatment are potentially more invasive. The goal of this study was to investigate whether this increased phenotype in surviving cells is facilitated by actin-rich, membrane-based structures known as invadopodia. METHODS A number of commercially available cell lines and glioblastoma cell lines obtained from patients were initially screened for the protein expression levels of invadopodia regulators. Gelatin-based zymography was also used to establish their secretory protease profile. The effects of radiation and temozolomide treatment on the glioblastoma cells were then investigated with cell viability, Western bl...
The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas
Cancer Drug Resistance, 2020
Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking, followed by radiation therapy with concurrent and adjuvant temozolomide treatment. The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy. Several mechanisms including inter-and intratumoral heterogeneity, the evolution of therapy-resistant clonal subpopulations, reacquisition of stemness in glioblastoma stem cells, multiple drug efflux mechanisms, the tumor-promoting microenvironment, metabolic adaptations, and enhanced repair of drug-induced DNA damage have been implicated in therapy failure. Extracellular vesicles (EVs) have emerged as crucial mediators in the maintenance and establishment of GBM. Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance. Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies. In this review, we discuss the various mechanisms of therapy resistance in GBM, highlighting the emerging role of EV-orchestrated drug resistance. Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.
Small extracellular vesicles as tumor biomarkers for glioblastoma
Molecular Aspects of Medicine, 2015
Small extracellular organelles such as exosomes and microvesicles are currently being studied as a novel way to track tumor progression, pseudoprogression, and treatment monitoring. Their role in intercellular communication shows potential in the treatment of even the most formidable cancers. Glioblastoma (GBM) is the most common malignancy of the brain and has no known cure. A large emphasis has been placed on trying to improve the prognosis of this aggressive primary brain tumor. It has recently been discovered that small extracellular vesicles, mainly exosomes and microvesicles, play a role in the cell signaling process that leads to uncontrollable cell growth indicative of a tumor state. Here we describe the role of exosomes and microvesicles as a tumor biomarker for tracking the progression of different types of cancer, with an emphasis on GBM.
Phenotype and Neuronal Cytotoxic Function of Glioblastoma Extracellular Vesicles
Biomedicines
Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor. Extracellular vesicles (EVs) released by tumor cells play a critical role in cellular communication in the tumor microenvironment promoting tumor progression and invasion. We hypothesized that GBM EVs possess unique characteristics which exert effects on endogenous CNS cells including neurons, producing dose-dependent neuronal cytotoxicity. We purified EVs from the plasma of 20 GBM patients, 20 meningioma patients, and 21 healthy controls, and characterized EV phenotypes by electron microscopy, nanoparticle tracking analysis, protein concentration, and proteomics. We evaluated GBM EV functions by determining their cytotoxicity in primary neurons and the neuroblastoma cell line SH-SY5Y. In addition, we determined levels of IgG antibodies in the plasma in GBM (n = 82), MMA (n = 83), and controls (non-tumor CNS disorders and healthy donors, n = 50) with capture ELISA. We discovered that GBM plasma EVs are smaller...
Cancer research, 2016
A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV ...