Players in glioma progression: Genomic exploration of glioma cell compartments

Abstract

Diffuse gliomas are malignant tumors of the central nervous system (CNS), characterized by infiltrative growth, high heterogeneity and poor prognosis. Characterization of the genetic alterations in these tumors is important for correct diagnosis, therapeutic approaches and overall patient survival. Based on genetic mutations, gliobastomas (GMB) can be divided into proneural, classical and mesenchymal subtypes. In this thesis, the potential value of a family of ‘inhibitor of differentiation’ proteins to differentiate between astrocytic and oligodendrocytic gliomas was determined. Glioma tumorigenicity is not only controlled by genetic alterations, interaction between tumor cells and cells of the non-tumor tissue are critical for glioma growth and aggressiveness. Non-tumor cells that are important for GBM progression are immune cells that enter the brain tumor and microglia. Microglia are the local immune cells of the CNS, essential for brain development, and the first cells to detect and respond to damage or danger. In this thesis, microglia from normal and tumor CNS tissue are characterized. Microglia were isolated from the CNS autopsy samples and gliomas, and their gene expression profiles were determined. Human microglia are very similar to mouse microglia but the effect of aging was very different. Microglia in diffuse gliomas are immune-suppressed and tumor-growth supportive, especially in tumors with poor clinical outcome. This data is the first extensive human microglia gene expression profile, from both physiological and pathological conditions. These results provide insight in glioma heterogeneity and the tumor-supportive properties of the non-tumor microenvironment, potentially leading to the identification of new therapeutic targets