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

SIMPLE SUMMARY: Glioblastoma (GBM) is one of the greatest challenges facing neuro-oncology today. Current treatments are far from satisfactory and, given the poor prognosis of the disease, therapeutic efforts are focused on palliative management rather than curative intervention. Here, we review the cellular heterogeneity of GBM, including tumor cells and microglia/macrophages among others, as well as the genetic, epigenetic and metabolic alterations controlling its initiation and progression. Then, we describe the genetic and xenotransplantation zebrafish models established in the last few years for the study of GBM physiopathology and for testing new drugs to improve the treatment of the disease. Taking this information into account, forthcoming studies using zebrafish models of GBM are expected to shed light on better diagnosis and treatments, thus providing hope for GBM patients. 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.