GBM's multifaceted landscape: highlighting regional and microenvironmental heterogeneity

Abstract

Gliomas are a heterogeneous group of tumors that show variable proliferative potential, invasiveness, aggressiveness, histological grading, and clinical behavior. In this review, we focus on glioblastoma multiforme (GBM), a grade IV glioma, which is the most common and malignant of primary adult brain tumors. Research over the past several decades has revealed the existence of extensive cellular, molecular, genetic, epigenetic, and metabolic heterogeneity among tumors of the same grade and even within individual tumors. Evaluation of different tumor types has shown that tumors with advanced grade and clinical aggressiveness also display enhanced molecular, cellular, and microenvironmental heterogeneity. From a therapeutic standpoint, this heterogeneity is a major clinical hurdle for devising effective therapeutic strategies for patients and challenges personalized medicine. In this review, we will highlight key aspects of GBM heterogeneity, directing special attention to regional heterogeneity, hypoxia, genomic heterogeneity, tumor-specific metabolic reprogramming, neovascularization or angiogenesis, and stromal immune cells. We will further discuss the clinical implications of GBM heterogeneity in the context of therapy.

Keywords: angiogenesis; glioblastoma; hypoxia; metabolism.

Fig. 1.

Schematic representation of events with respect to vasculature, metabolism, and cellular heterogeneity in GBM. GSC, glioma stem cell. (A) Normal tissue displaying regular blood supply. (B) In LGAs, the slight increase in hyperproliferation of cancer cells is associated with increased microvessel proliferation. (C) In GBM, there is a marked increase in abnormal vasculature that further dictates regional heterogeneity. The texts in boxes display salient features of each of the regions commonly reported in GBM.