An active role for neurons in glioma progression: making sense of Scherer's structures

Abstract

Perineuronal satellitosis, the microanatomical clustering of glioma cells around neurons in the tumor microenvironment, has been recognized as a histopathological hallmark of high-grade gliomas since the seminal observations of Scherer in the 1930s. In this review, we explore the emerging understanding that neuron‒glioma cell interactions regulate malignancy and that neuronal activity is a critical determinant of glioma growth and progression. Elucidation of the interplay between normal and malignant neural circuitry is critical to realizing the promise of effective therapies for these seemingly intractable diseases. Here, we review current knowledge regarding the role of neuronal activity in the glioma microenvironment and highlight critical knowledge gaps in this burgeoning research space.

Fig. 1

An image from Dr. Scherer’s 1938 analysis depicts clusters of glioma cells around neuronal soma. Magnified and schematized inset added for clarity. Neuronal soma, yellow. Glioma cells, green.

Fig. 2

Schematic illustrating a bidirectional relationship between normal neural cells and their malignant glioma counterparts. Activity-regulated factors including a secreted form of neuroligin-3 (sNLGN3) from normal OPCs (blue) and neurons (yellow) and neurotrophins such as BDNF fuel the growth of glioma. Glioma cells (green), in turn, secrete glutamate and synaptogenic factors that increase neuronal excitability and probability of firing action potentials.