Glioblastoma Heterogeneity and More Accurate Representation in Research Models

Abstract

In their study, Inoue et al. characterized two types of orthotopic brain tumors obtained from cells of a single parental spontaneous glioblastoma (GB) implanted in a murine model. Despite their common origin, these tumors had striking differences in important features, such as angiogenesis dependence and invasive patterns. The finding that a single tumor is able to give rise to two distinct cell types and form different types of brain tumors speaks to the heterogeneity of GBs and shows the possibility of finding different tumor-initiating cells within a tumor. In adult humans, GB is the most common and lethal primary malignancy of the central nervous system. GB represents approximately 50% of all gliomas. Despite the best treatment modalities presently available, GBs have a median survival of only 14–16 months and a 2-year survival rate of < 10%−15% (26). These tumors are refractory to the combination of surgical resection, radiation, and chemotherapy. Morphologic characteristics of GBs include diffuse infiltration, angiogenesis, and necrosis; molecular characteristics include chromosomal aberrations and genomic instability. Histopathologically, GBs are poorly delineated tumors with abundant undifferentiated mitotic cells and nuclear atypia. Necrosis and microvascular proliferation are also present (17). GBs are characteristically heterogeneous and vary with respect to histologic findings and distinct chromosomal and genetic aberrations (16, 19). A review on the subject by Bonavia et al. (4) deepened the understanding of the origin and maintenance mechanisms of such heterogeneity. The concept of clonal evolution applies to tumor clonal cell populations, which under selective therapeutic or pathologic pressure acquire properties to resist challenges and survive. A second concept that may explain cancer heterogeneity is associated with the role of cancer stem cells (CSCs), a poorly differentiated subpopulation of cells with tumor initiation capabilities. These two concepts are not mutually exclusive because CSCs can undergo a process of clonal evolution as they proliferate (12). The presence of different tumor cells capable of reproducing the pathology in orthotopic models as reported by Inoue et al. may be explained by this phenomenon.