Evolution of Experimental Models in the Study of Glioblastoma: Toward Finding Efficient Treatments

Abstract

Glioblastoma (GBM) is the most common form of brain tumor characterized by its resistance to conventional therapies, including temozolomide, the most widely used chemotherapeutic agent in the treatment of GBM. Within the tumor, the presence of glioma stem cells (GSC) seems to be the reason for drug resistance. The discovery of GSC has boosted the search for new experimental models to study GBM, which allow the development of new GBM treatments targeting these cells. In here, we describe different strategies currently in use to study GBM. Initial GBM investigations were focused in the development of xenograft assays. Thereafter, techniques advanced to dissociate tumor cells into single-cell suspensions, which generate aggregates referred to as neurospheres, thus facilitating their selective expansion. Concomitantly, the finding of genes involved in the initiation and progression of GBM tumors, led to the generation of mice models for the GBM. The latest advances have been the use of GBM organoids or 3D-bioprinted mini-brains. 3D bio-printing mimics tissue cytoarchitecture by combining different types of cells interacting with each other and with extracellular matrix components. These in vivo models faithfully replicate human diseases in which the effect of new drugs can easily be tested. Based on recent data from human glioblastoma, this review critically evaluates the different experimental models used in the study of GB, including cell cultures, mouse models, brain organoids, and 3D bioprinting focusing in the advantages and disadvantages of each approach to understand the mechanisms involved in the progression and treatment response of this devastating disease.

Targeting Protein Kinase C in Glioblastoma Treatment

“…Finally, EGFR (epidermal growth factor receptor) expression, without loss of PTEN (phosphatase and tensin homolog), explains the sensitivity of gliomas to tyrosine kinase inhibitors [28]. In conclusion, the use of molecular traits is assisting with the classification of gliomas, the high biological heterogeneity of which require the use of different experimental models for their study [29] and different strategies of clinical management.…”

A Fast and Efficient Approach to Obtaining High-Purity Glioma Stem Cell Culture

“…Brain organoids are a new approach for GBM modeling ( Qian et al, 2016 ). Comparing to the two-dimensional culture of GSC cells, the organoid culture system acted as a 3D system may reproduce a better niche for GBM study ( Gomez-Oliva et al, 2020 ). Organoid models are very useful for studies of essential tumor biology and also suitable for preclinical investigations, such as drug screening and analysis of antitumor effects accompanied by a rapid and safety test in the same system ( da Hora et al, 2019 ).…”

GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment

“…Intriguingly, subcutaneous GBM tumors have been reported to show higher density of fibroblast-like cells, type I collagen, and fibrillar collagen than the orthotopic counterpart [ 47 ], which may arise due to ECM composition in normal brain tissue being highly specialized and distinct from that of any other tissues in the body [ 48 ]. It should also be noted that both subcutaneous and orthotopic xenograft tumor models derived from a human cancer cell line cannot fully recapitulate the desmoplastic tumor microenvironment of clinical tumors due to many of the integral oncogenesis process along with key environmental factors (e.g., cancer-associated fibroblasts) being absent or of murine origin, thus exhibiting different characteristics to those observed in patient tumor samples [ 42 , 49 , 50 , 51 , 52 ]. As these microenvironmental factors play an integral role in multiple biological processes such as desmoplasia and progression of clinical tumors, a more in-depth evaluation of the combinatory effect of GM101 and HDACi will be conducted in patient-derived xenograft models or those utilizing patient-derived tumor explants to obtain more clinically relevant data in a future study.…”