Abstract

Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of the β-subunit of Na, K-ATPase have been implicated in regulating cellular dynamics, particularly during cancer progression. The aim of this study was to determine the Na, K-ATPase β subunit isoform subcellular expression patterns in all cell types responsible for microenvironment heterogeneity of GBM using immunohistochemical analysis. All three isoforms, β1, β2/AMOG (Adhesion Molecule On Glia) and β3, were found to be expressed in GBM samples. Generally, β1 isoform was not expressed by astrocytes, in both primary and secondary GBM, although other cell types (endothelial cells, pericytes, telocytes, macrophages) did express this isoform. β2/AMOG and β3 positive expression was observed in the cytoplasm, membrane and nuclear envelope of astrocytes and GFAP (Glial Fibrillary Acidic Protein) negative cells. Interestingly, differences in isoforms expression have been observed between primary and secondary GBM: in secondary GBM, β2 isoform expression in astrocytes was lower than that observed in primary GBM, while the expression of the β3 subunit was more intense. These changes in β subunit isoforms expression in GBM could be related to a different ionic handling, to a different relationship between astrocyte and neuron (β2/AMOG) and to changes in the moonlighting roles of Na, K-ATPase β subunits as adaptor proteins and transcription factors.

Highlights

  • Glioblastoma multiforme (GBM) is the most aggressive of malignant glioma

  • GBM consists of the following cell types: glioma stem cells (GSCs), astrocytes, vascular cells [8,9], telocytes, immune cells (glioma-infiltrating myeloid cells (GIMs) or tumor-associated macrophages (TAMs), and remaining neurons

  • Immunoperoxidase staining on paraffin-embedded tissue sections was used to localize Na, K-ATPase β1 isoform in samples from GBM patients

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Summary

Introduction

Glioblastoma multiforme (GBM) is the most aggressive of malignant glioma. Even after state-of-the art treatment, the median survival of patients is less than one year and outcomes give overall survival (OS) as less than 10% at two years, decreasing to less than 2% at five years [1,2,3]. Heterogeneity of cells in GBM is a key factor for the low effectiveness of treatments [4]. GBM presents epigenetically and genetically different cell sub-populations within a single tumor that contributes to growth, progression and treatment failure. Primary GBM arises suddenly in older patients after a brief clinical history and is characterized by rapid progression and short survival time [6]. Secondary GBM are more frequent in younger patients and evolve from a diffuse or an anaplastic astrocytoma [7]. GBM consists of the following cell types: glioma stem cells (GSCs), astrocytes, vascular cells (endothelial and pericytes) [8,9], telocytes (a characteristic type of stromal cell, with thin prolongations up to hundreds of microns, ranging from the optic to electronic microscopy resolving power [10,11]), immune cells (glioma-infiltrating myeloid cells (GIMs) or tumor-associated macrophages (TAMs), and remaining neurons

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