Cell-Population Dynamics in Diffuse Gliomas during Gliomagenesis and Its Impact on Patient Survival

SIMPLE SUMMARY: There is only a relatively small set of tools for the diagnosis and therapy of diffuse gliomas. To solve this problem, intratumoral heterogeneity has become the most important research topic. In this study, through the prism of cell-population heterogeneity in diffuse gliomas, using flow cytometry, multimeric FISH, immunofluorescence, PCR, and cell cultures, we comparatively examined the dynamics of cell populations’ quantitative and qualitative transformations in diffuse gliomas. For the first time, we identified mesenchymal-like cellular transformation in astrocytomas and oligodendrogliomas as possibly the key mechanism of malignancy. In the case of glioblastoma, it was shown for the first time that mesenchymal transformation is of a deeper nature, passing through the stem-cell link. The transformation severity influenced the prognosis of overall and relapse-free patient survival. ABSTRACT: Diffuse gliomas continue to be an important problem in neuro-oncology. To solve it, studies have considered the issues of molecular pathogenesis from the intratumoral heterogeneity point. Here, we carried out a comparative dynamic analysis of the different cell populations’ content in diffuse gliomas of different molecular profiles and grades, considering the cell populations’ functional properties and the relationship with patient survival, using flow cytometry, immunofluorescence, multiparametric fluorescent in situ hybridization, polymerase chain reaction, and cultural methods. It was shown that an increase in the IDH-mutant astrocytomas and oligodendrogliomas malignancy is accompanied by an increase in stem cells’ proportion and mesenchymal cell populations’ appearance arising from oligodendrocyte-progenitor-like cells with cell plasticity and cells’ hypoxia response programs’ activation. In glioblastomas, malignancy increase is accompanied by an increase in both stem and definitive cells with mesenchymal differentiation, while proneuronal glioma stem cells are the most likely the source of mesenchymal glioma stem cells, which, in hypoxic conditions, further give rise to mesenchymal-like cells. Clinical confirmation was a mesenchymal-like cell and mesenchymal glioma stem cell number, and the hypoxic and plastic molecular programs’ activation degree had a significant effect on relapse-free and overall survival. In general, we built a multi-vector model of diffuse gliomas’ pathogenetic tracing up to the practical plane.