Glioblastoma microenvironment-from biology to therapy

Abstract

Glioblastoma (GBM) is the most aggressive primary brain cancer. These tumors exhibit high intertumoral and intratumoral heterogeneity in neoplastic and nonneoplastic compartments, low lymphocyte infiltration, and high abundance of myeloid subsets that together create a highly protumorigenic immunosuppressive microenvironment. Moreover, heterogeneous GBM cells infiltrate adjacent brain tissue, remodeling the neural microenvironment to foster tumor electrochemical coupling with neurons and metabolic coupling with nonneoplastic astrocytes, thereby driving growth. Here, we review heterogeneity in the GBM microenvironment and its role in low-to-high-grade glioma transition, concluding with a discussion of the challenges of therapeutically targeting the tumor microenvironment and outlining future research opportunities.

Keywords: glial cells; glioblastoma; glioma stem cell; lymphoid cells; myeloid cells; stem cell niche; tumor microenvironment.

Figure 1.

The tumor core and periphery. (A) Illustration of the perivascular area (PVA). Compromised blood–brain barrier and increased chemokine gradients facilitate the recruitment of monocytes, neutrophils, and T-cells into the perivascular region (PVR), where they form close interactions with each other and other cells in the perivascular niche, including astrocytes, pericytes, endothelial cells, tumor cells, and GSCs, to promote tumor growth and therapy resistance. (B) Illustration of the hypoxic area. The hypoxic pseudopalisading rim and the necrotic core are key features of GBM and are home to therapy-resistant GSCs. While neutrophils are enriched in the necrotic core, the rim is enriched with MDMs that suppress the T-cell function. The hypoxic areas show an increased presence of MES-like tumor cells. (C) Illustration of the invasive/infiltrative edge at the tumor periphery. GBM cells migrate along blood vessels at the invasive margin. Microglial cells align with invading GBM cells and facilitate their invasion. In addition, they create a peritumoral ring. Primary cell types constituting the microenvironment at the invasive edge of GBM are endothelial cells, pericytes, activated microglia, reactive astrocytes, and neurons. Invading GBM cells elude surgical resection and are partly accountable for tumor recurrence.

Figure 2.

Illustration of the cellular compositions and phenotypes of tumor microenvironments in low-grade versus high-grade gliomas. Blue arrows indicate a decrease and red arrows indicate an increase in various molecule(s) that define phenotypic changes in the corresponding cells. The illustration demonstrates that in contrast to low-grade gliomas, gigh-grade gliomas exhibit high angiogenesis, a more dysfunctional BBB, increased infiltration of immunosuppressive myeloid cells, and exhausted T-cells.