Peritumoral Microenvironment in High-Grade Gliomas: From FLAIRectomy to Microglia-Glioma Cross-Talk

Abstract

Cellular composition and molecular signatures of the glioma core compared with infiltrative margins are different, and it is well known that the tumor edge is enriched in microglia. In this review of the literature, we summarize the role of the peritumoral area in high-grade gliomas (HGGs) from surgical and biological points of view. There is evidence on the dual role of microglia in HGGs-a scavenger-tumoricidal role when microglia are activated in an M1 phenotype and a role favoring tumor growth and infiltration/migration when microglia are activated in an M2 phenotype. Microglia polarization is mediated by complex pathways involving cross-talk with glioma cells. In this scenario, extracellular vesicles and their miRNA cargo seem to play a central role. The switch to a specific phenotype correlates with prognosis and the pathological assessment of a specific microglial setting can predict a patient's outcome. Some authors have designed an engineered microglial cell as a biologically active vehicle for the delivery of intraoperative near-infrared fluorescent dye with the aim of helping surgeons detect peritumoral infiltrated areas during resection. Furthermore, the pharmacological modulation of microglia-glioma cross-talk paves the way to more effective therapies.

Keywords: 5-ALA; extracellular vesicle; glioblastoma; glioma; immunomodulation; mTOR; microRNA; microglia; supratotal resection.

Figure 1

(A) Histological examination of glioblastoma (GBM) tissue sample showing a central focus of pseudopalisading necrosis, enriched with hemosiderin deposits (hematoxilin and eosin; original magnification 100×). (B) Immunohistochemical tests showing an abundant microglial activation, consisting of numerous clusters of differentiation (CD)163-positive glioma-associated microglia and macrophages (GAMs) that crowd the hypercellular zone surrounding the pseudopalisading necrosis (immunoperoxidase staining; original magnification 100×). (C) Histological detail showing fragments of unaffected brain parenchyma (arrows) at the periphery of a “classic-type” GBM, diffusely infiltrated by glioma cells (hematoxilin and eosin; original magnification 100×). (D) Immunohistochemical staining with CD163 highlights the presence of marked microglial activation with the M2-like phenotype at the invasive front of the tumor (immunoperoxidase staining; original magnification 100×).

Figure 2

Schematic representation of miRNA-mediated cross-talk between GBM and microglia cells. (A) Effects of the cross-talk between GBM and microglia in pathological conditions, inducing microglial M2 polarization. (B) Suggested miRNA-mediated therapeutic strategies inducing the switch from M2 to M1 microglial polarization. Refer to the text for a more detailed description. MG = microglia; GBM = glioblastoma.

Figure 3

Images show an intraoperative view of peritumoral areas. In the neuronavigational view, the tracer is placed in the FLAIR hyperintensity zone beyond the enhancing nodule (EN). In the right upper image, there is the corresponding and apparently normal tissue under white light and in the image at the bottom the same surgical site under blue light revealing the presence of lava-like fluorescence.