The multifaceted mechanisms of malignant glioblastoma progression and clinical implications

Abstract

With the application of high throughput sequencing technologies at single-cell resolution, studies of the tumor microenvironment in glioblastoma, one of the most aggressive and invasive of all cancers, have revealed immense cellular and tissue heterogeneity. A unique extracellular scaffold system adapts to and supports progressive infiltration and migration of tumor cells, which is characterized by altered composition, effector delivery, and mechanical properties. The spatiotemporal interactions between malignant and immune cells generate an immunosuppressive microenvironment, contributing to the failure of effective anti-tumor immune attack. Among the heterogeneous tumor cell subpopulations of glioblastoma, glioma stem cells (GSCs), which exhibit tumorigenic properties and strong invasive capacity, are critical for tumor growth and are believed to contribute to therapeutic resistance and tumor recurrence. Here we discuss the role of extracellular matrix and immune cell populations, major components of the tumor ecosystem in glioblastoma, as well as signaling pathways that regulate GSC maintenance and invasion. We also highlight emerging advances in therapeutic targeting of these components.

New Dual P-Glycoprotein (P-gp) and Human Carbonic Anhydrase XII (hCA XII) Inhibitors as Multidrug Resistance (MDR) Reversers in Cancer Cells

“…This feature makes the compounds particularly promising as chemosensitizer agents in the most aggressive and drug-resistant tumors that coexpress both P-gp and hCA XII. This is the case of tumors rich in stem cells, which are often responsible for tumor relapse, metastization, and generation of drug-resistance clones, − or hypoxic tumors that are the most invasive and resistant to the conventional therapies in use, − where the transcription factor HIF-1α transcriptionally upregulates P-gp and hCA XII …”

Epithelia delimits glial apical polarity against mechanical shear to maintain glia-neuron - architecture

“…Interestingly, components of this pathway (BAG2, FGFR, Spectrins) also regulate cell polarity and cancer epithelial-mesenchymal transitions (Antony et al, 2019; Lu and Lu, 2021; Perez-Moreno et al, 2003). Their levels track aggressiveness of cancers like glioblastoma (Behl, 2016; Gentilella and Khalili, 2011; Qin et al, 2021) that have abnormal vascularization and ECM mechanical properties (Khoonkari et al, 2022; Sun and Kim, 2022). This raises the possibility that this molecular cascade may broadly transduce epithelia-glia mechanobiological coupling, suggesting that its role in epithelia-glia signaling in sensorineural health, aging and disease warrants further inquiry.…”

“…and ECM mechanical properties (Khoonkari et al, 2022;Sun and Kim, 2022). This raises the possibility that this molecular cascade may broadly transduce epithelia-glia mechanobiological coupling, suggesting that its role in epithelia-glia signaling in sensorineural health, aging and disease warrants further inquiry.…”

Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain

“…Silencing the apelin Signaling pathway either by knocking down or blocking the APLNR reduces tumor volume, vascularization, and proliferation [ 89 ]. GSC are in a quiescent state maintained by the vascular niche in the tumor, which is the main reason for the inefficiency of chemotherapies [ 90 ]. Interestingly, applying an antagonist of APLNR in combination with chemotherapies improves the response and decreases the GSC numbers.…”