Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

Abstract

Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood–brain–barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBM.

Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders

“…As vertebrates, zebrafish, and human genomes show a high homology, about 80% of genes associated with diseases in patients are conserved in zebrafish ( Kalueff et al, 2014 ). Notably, many CNS-related disorders have been successfully modeled in the past and some recent reviews have compiled an exhaustive list of zebrafish models of Amyotrophic Lateral Sclerosis (ALS) ( Braems et al, 2021 ), Hereditary Spastic Paraplegia (HSP) ( Naef et al, 2019 ; Quelle-Regaldie et al, 2021a , b ), Epilepsy ( Rosch et al, 2019 ; Gawel et al, 2020 ), Autism Spectrum Disorder (ASD) ( Meshalkina et al, 2018 ; de Abreu et al, 2020 ), Alzheimer’s Disease (AD) ( Saleem and Kannan, 2018 ), Parkinson’s Disease (PD) ( Unal and Emekli-Alturfan, 2019 ; Najib et al, 2020 ), Huntington’s and Prion-related diseases ( Wang et al, 2021 ), Serotonin syndrome (SS) ( Stewart et al, 2013 ), and Glioblastoma ( Reimunde et al, 2021 ). In this context, our group pioneered the generation of several models of CNS genetic disorders, caused by mutations in gabra1 ( Samarut et al, 2018 ), gabrg2 ( Liao et al, 2019 ), depdc5 ( Swaminathan et al, 2018 ), glra1 ( Samarut et al, 2019 ), or gldc ( Riche et al, 2018 ), and these mutants display clinically-relevant phenotypes such as seizures, ataxic motor phenotypes or hypotonia.…”

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review)

“…In GBM, several pathways have been frequently found to be altered, including the PI3K/AKT/mTOR, p53 and Rb pathways (39,49), making them potential targets for GBM treatment. Although there is increasing interest in targeting the tumour microenvironment, such as blood vessels, the monocyte-macrophage-microglia compartment and T cells (93), improved clinical trial design by including pharmacodynamic endpoints in patient populations is required to optimise this type of treatment.…”

Current Advances in Immunotherapy for Glioblastoma Multiforme and Future Prospects

“…Another way is by inhibiting the adipocyte enhancer-binding protein-1 (AEBP1) signaling pathway using ACT001 for the treatment of GBM [ 63 ]. In addition, it is better to find more effective animal models to better understand the treatment of GBM, such as the recent discovery of the zebrafish model, as it has a similar brain structure to that of humans [ 64 ]. It is also apparent that in order to treat GBM efficiently, combination treatments are required by combining surgery, radiation, chemotherapy, and various immunotherapies together [ 65 , 66 ].…”