Molecular and Clinical Insights into the Invasive Capacity of Glioblastoma Cells

Abstract

The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

“…GB is the most common malignant primary brain tumor, driven by complex signaling pathways and particularly difficult to treat [4,35]. Although the current therapeutic protocols have been refined, GB remains a fatal human cancer, in which the estimated survival is 8 to 15 months [2,35].…”

“…Glioblastoma multiforme (GB) is the most frequent and malignant primary tumor of the central nervous system [1], with a median overall survival of about 15 months [2][3][4]. GB is particularly difficult to treat, given its intense vascularization, rapid progression and high resistance to standard…”

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma

“…This infiltration cannot be visualized by MRI. Evidence suggests that GBM-associated macrophages aid in the infiltration of GBM cells throughout the brain [94]. It is not currently known if immunotherapeutics, including ICIs, have any effect on these infiltrating cells or indeed whether GBM-targeted immune cells will be able to move through the brain to reach these cells.…”

Leptomeningeal Spread in Glioblastoma: Diagnostic and Therapeutic Challenges

“…The leptomeningeal seeding from cortical areas is preceded by subpial spread as an intermediary step [5, 10, 17, 35]. During this migratory process, GBM cells secrete multiple proteases degrading the extracellular matrix (e.g., MMP‐1, ‐2, ‐7, ‐9, ‐14, and ‐19 with a critical role of MMP‐2 and ‐9) to create a moving space [37–42] and express multiple adhesion‐migration proteins (e.g., glycosylated chondroitin sulfate proteoglycans, fibronectin, fascin, and integrins) [35, 39, 41, 43]. Both molecule classes, working synergistically with cytoskeleton, allow tumor cell migration toward leptomeninges and CSF [5, 18, 28, 30, 35, 39, 41, 43–45].…”