Glioblastoma Microenvironment and Invasiveness: New Insights and Therapeutic Targets

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain cancer in adults. Without treatment the mean patient survival is approximately 6 months, which can be extended to 15 months with the use of multimodal therapies. The low effectiveness of GBM therapies is mainly due to the tumor infiltration into the healthy brain tissue, which depends on GBM cells’ interaction with the tumor microenvironment (TME). The interaction of GBM cells with the TME involves cellular components such as stem-like cells, glia, endothelial cells, and non-cellular components such as the extracellular matrix, enhanced hypoxia, and soluble factors such as adenosine, which promote GBM’s invasiveness. However, here we highlight the role of 3D patient-derived glioblastoma organoids cultures as a new platform for study of the modeling of TME and invasiveness. In this review, the mechanisms involved in GBM-microenvironment interaction are described and discussed, proposing potential prognosis biomarkers and new therapeutic targets.

Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel

“…Glioma stem cells (GSCs) constitute a self-renewing and slow-dividing sub-population within GBM. 25,26 They recapitulate the heterogeneity of their parent glioma tissues and show similarity in drug resistance and refraction to treatment to clinical GBM cases. As shown in Fig.…”

Intrinsic and Microenvironmental Drivers of Glioblastoma Invasion

“…Hyaluronan (HA), one of the primary brain ECM components, seems to facilitate cell migration by binding to its cognate receptor, CD44 [ 60 , 61 , 62 , 63 ]. Similarly, osteopontin (OPN) acts as a CD44 ligand, triggering its intracellular signaling and CREB gene expression that is responsible for glioma cell perivascular migration and invasion and contributes to maintaining a stem-like phenotype [ 64 , 65 ]. Furthermore, fibronectin, which is highly enriched in mesenchymal-type gliomas, stimulates collective invasion by increasing the cohesion of GBM cells [ 65 , 66 ], while collagen molecules in the perivascular niche promote tumor invasiveness through upregulation of integrin and PI3K/Akt signaling [ 59 , 67 , 68 ].…”

“…Similarly, osteopontin (OPN) acts as a CD44 ligand, triggering its intracellular signaling and CREB gene expression that is responsible for glioma cell perivascular migration and invasion and contributes to maintaining a stem-like phenotype [ 64 , 65 ]. Furthermore, fibronectin, which is highly enriched in mesenchymal-type gliomas, stimulates collective invasion by increasing the cohesion of GBM cells [ 65 , 66 ], while collagen molecules in the perivascular niche promote tumor invasiveness through upregulation of integrin and PI3K/Akt signaling [ 59 , 67 , 68 ]. Tumors also upregulate several different integrins to stimulate migration and dynamic interactions of the cytoskeleton and the ECM [ 66 , 69 , 70 , 71 ].…”

“…Finally, there is evidence of the involvement of different laminin isoforms in promoting glioma invasion. Laminin-2 and laminin-5 are preferentially upregulated in invasive GBM areas, while laminin-8 silencing has resulted in significant impairment of GBM invasion [ 65 , 72 , 73 , 74 ].…”

Protumorigenic role of the atypical cadherin FAT1 by the suppression of PDCD10 via RelA/miR221‐3p/222‐3p axis in glioblastoma

“…Understanding the molecular aberrations in tumors has helped in more precise sub‐grouping of the tumors, with improved diagnosis and management 21 . However, the challenges in the treatment and management of GBM persist due to tumor heterogeneity, tumor invasiveness and aggressive tumor growth and relapse 24 . Hence, there is an unmet need for uncovering newer molecular mechanisms that could be harnessed for developing novel therapeutic approaches for GBM.…”