A neurocentric perspective on glioma invasion

Abstract

Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood-brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease.

Figure 1. Glioma cells associate with blood vessels in the brain

Most glioma cells that have migrated away from the main tumour mass into the brain parenchyma can be found on blood vessels. Examples of the patient-derived glioma line GBM22 (part a) and of the human glioma cell line D54 (part b) are shown, with high-magnification zooms of the boxed areas on the right. In both examples, glioma cells closely associate with blood vessels in the brain. Human glioma cells are labelled with enhanced green fluorescent protein (EGFP), and murine vessels are labelled with a CD31-specific antibody.

Figure 2. A hydrodynamic model of glioma cell migration

a | Glioma cells encounter spatial barriers (for example, other cells) as they migrate along blood vessels through the brain. Gliomas express various channels, including Cl⁻ channel protein 3 (ClC3; a voltage-gated Cl⁻ channel), Ca²⁺-activated K⁺ channel KCa3.1 and aquaporins. b | Upon stimulation of G protein-coupled receptors (GPCRs), there is a rise in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in glioma cells, leading to Ca²⁺-dependent activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-dependent ClC3 and KCa3.1 channel opening. This leads to the efflux of Cl⁻ and K⁺, obligating water to flow down its osmotic gradient and leave the cell. This volume decrease enables glioma cells to decrease cytoplasmic volume and squeeze into small spaces. c | After passing a spatial barrier, glioma cells can regain volume through ion influx through the Na⁺–K⁺–Cl⁻ cotransporter 1 (NKCC1) and acid-sensing ion channel 1 (ASIC1). BK, bradykinin.

Figure 3. Glioma cells break down the blood–brain barrior

a | In the healthy brain, astrocytic endfeet surround blood vessels. Vascular endothelial cells form the blood–brain barrier (BBB) though tight junctions, trapping cells and serum components in the vascular lumen. b | Glioma cells migrate along blood vessels, leading to displacement of astrocytic endfeet, degradation of tight junctions on endothelial cells and breakdown of the basement membrane surrounding blood vessels. In turn, serum components leak into the neural parenchyma.

Figure 4. Glioma cells displace astrocytic endfeet from blood vessels

Electron micrographs of blood vessels (V) that are normally covered by astrocyte endfeet (A) (part a) can be partially (part b) or completely (parts c and d) ensheathed by patient-derived glioma cell lines GBM14 (part b) and GBM22 (parts c and d) glioma cells (G).