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.

Keywords: Extracellular matrix; Glioblastoma; Glioma stem cell; Immune cell; Invasion; Tumor microenvironment.

Fig. 1

Potential therapeutic targets in the tumor ecosystem of GBM. ECM: extracellular matrix, GSC: glioma stem cell

Fig. 2

Reorganization of the extracellular matrix in GBM. Left: normal brain ECM components. Right: the changes in ECM composition and signaling pathways involved in increased structural stiffness, cell–cell information exchange, and tumor invasion

Fig. 3

TAMs contribute to tumor growth and infiltration. By secreting cytokines and growth factors: TGF-β, IL-10, IL-6, IL-1β, pleiotrophin, EGF, and VEGF, TAMs can promote tumor cell proliferation, angiogenesis, ECM reorganization, and immunosuppression. By secreting enzymes (MMPs), TAMs can assist tumor cell migration and invasion. Approaches used for TAM-targeted therapeutics include re-education of phenotypes, signaling pathway inhibition, drugs bypassing the heterogeneity, and cell subpopulation depletion

Fig. 4

T cell dysfunction in GBM. Immunosuppressive cells (TAMs, Tegs, MDSCs, and tolerogenic DCs) and inhibitory molecules (PGE2, TGF-β, IL-10, and IL-6) induce cytotoxic T cells into the exhausted state. Exhaustion makers (PD-1, CTLA-4, Tim3, and LAG3) are upregulated in dysfunctional T cells. Tumor cells expressing mutant genes (PTPN11, PTEN, and BRAF) exacerbate T cell anergy. The abnormal signaling pathway (AKT/mTOR) activation promotes tumor growth and invasion. CAR-T cells with modified TCRs targeting IL-13Rα2, HER2, EphA2, or EGFRvIII have been tested in clinical trials for GBM. New antigens for CAR-T cells tested in animal models include HABP, GD2, Fn14, and B7-H3. Targets used for immune checkpoint blockade therapies include CTLA-4, PD-1, and PD-L1. Tolerogenic DCs and tDCs

Fig. 5

Plasticity in GSC phenotype and relevant therapeutic strategies. Four core transcription factors, POU3F2, SALL2, SOX2, and OLIG2 are sufficient to reprogram differentiated glioma cells (DGCs) into GSCs. There are four major cellular states of GBM cells including neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like), and mesenchymal like (MES-like) states within one GBM sample. The relative frequencies of each state are associated with genetic alterations in CDK4, PDGFRA, EGFR, and NF1 that each mutation favors a state. Based on the feature of GSCs, several therapeutic approaches are being evaluated including antibodies (Abs), CAR-T cells, inhibitors, cancer vaccines, and induction of GSC differentiation. CDK inhibitors that lead to cell growth arrest can be incorporated into GSC-based therapy regimens