A review of gliomas-related proteins. Characteristics of potential biomarkers

Abstract

Brain tumors are one of the most commonly diagnosed cancers of the central nervous system. Of all diagnosed malignant tumors, 80% are gliomas. An unequivocal diagnosis of gliomas is not always simple, and there is a great need for research to find new treatment options and diagnostic approaches. This paper is focused on the glioma-related protein profiles as compared to healthy brain tissue, which is reflected in multiple correlations between biological aspects that influence proliferation, apoptosis evasion and the invasiveness of neoplastic cells. The work presents the possibilities of facilitating clinical practice with proteomic biomarkers, which offer a wider diagnostic spectrum and reduce the margin of mistake in histopathological or imaging diagnostic methods. In fact, many changes in the body's homeostasis can be overlooked due to the lack of symptoms or their non-specificity. Nevertheless, a single marker has limited reliability in distinguishing a particular tumor subtype, since the increased or decreased level of the protein of interest may differ between the stages or locations of the tumor. Moreover, the correlations between proposed proteins - presented in this paper - may help clinicians to choose the most optimal therapy, and estimate its effectiveness, or indicate new therapeutic targets affecting disrupted biochemical pathways.

Keywords: GBM; biochemistry; biomarkers; glioma; proteomics.

Figure 1

Pathways affecting glioma cell proliferation. Marked proteins were proposed as glioma biomarkers, which affect the most basic pathways responsible for cell proliferation. Both, mutated EGFR and EGFRvIII, are overexpressed in glioma cells, affecting MAPK/ERK, PI3K/AKT/mTOR and JAK-STAT pathways by modulating them. Moreover, decreased levels of PTEN inhibitor affect PI3K/AKT/mTOR pathway, while elevated levels of BRAF affect MAPK/ERK pathway. Elevated levels of PDGFRα receptor protein modulate MAPK/ERK and PI3K/AKT/mTOR pathways. SOCS3 interacts with JAK-STAT pathway by direct inhibition of the catalytic domain of JAK. Increased levels of SOCS3 lead to pathway impairment and promotion of neovascularization and tumorigenesis. Increased levels of BIRC5 protein disrupt the caspase cascade, leading glioma cells to avoiding apoptosis. ATRX and DAXX are encoding two subunits of a chromatin remodeling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres. Presence of H3F3A/ATRX-DAXX mutations is associated with alternative lengthening of telomeres. Overexpression of c-Myc is associated with metabolism aberrations leading to uncontrolled proliferation, growth, and survival of tumor cells. High expression of GFAP significantly affects growth and cell division.

Figure 2

Pathways for glioma immunology interactions. Marked proteins were proposed as glioma biomarkers, which affect the most basic pathways responsible for cell immunology. MAPK/ERK and PI3K/AKT/mTOR pathways are over-modulated by CD44 overexpression, but only the latter is also affected by CD133 overexpression. Moreover, MAPK/RAS and JAK-STAT signaling pathways are modulated by the presence of IL-13Rα2. Elevated levels of mutated p53 proteins, not correlated with the mentioned pathways, are responsible for inhibition of cell apoptosis.