Importance of GFAP isoform-specific analyses in astrocytoma

Abstract

Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.

Keywords: GFAP; GFAP variants; GFAPδ; astrocytoma; biomarker; glioma; intermediate filaments.

Figure 1

The GFAPδ/α ratio distinguishes astrocytoma subpopulations. Overview of low‐ (left panel) and high‐grade (right panel) astrocytoma and differences in the heterogeneous GFAP positive cell population. High‐grade astrocytoma (right panel) is characterized by increased mitosis and cell density, necrosis (black area) and vascularization (red vessels). Invasive astrocytoma cells use white matter tracts, blood vessels and meninges as a surface to migrate on (Claes, Idema, & Wesseling, 2007). GFAP levels in blood are specifically associated with grade IV astrocytoma. In both high‐ and low‐grade astrocytoma, the GFAP positive cell population is highly heterogeneous and contains cells with various functions (e.g., proliferating, quiescent, invasive, and static). GFAP negative areas are more often found in the center of high‐grade tumors (orange arrows). The GFAPδ isoform distinguishes astrocytoma subpopulations of cells (a, b), and as the GFAPδ/α ratio is increased in grade IV astrocytoma, this subpopulation is most likely larger in these tumors (b). GFAP protein and GFAP positive cells in blood of patients are associated with high‐grade astrocytoma and might contain different levels of GFAP isoforms (c). Similarly, invading cells that, for example, invade the meninges (connective tissue) might consist of a specialized GFAP network that equips them for this behavior (d)