Figure 1. The complexity of inter- and intratumoral heterogeneity in glioblastoma.

(A) Heterogeneity between individual patient tumors stems from both the cell of origin and the subsequent major epigenetic and genetic alterations. These variations produce different types of tumor-initiating cells (TICs). (B) TICs expand and establish genetically divergent clonal cell populations. During this clonal evolution process, cellular offspring acquire diverse genetic alterations and engender a variety of clones. Cells with similar types of genetic alterations exist in close spatial proximity, but their invasive properties will lead to clonal mixing and normal brain invasion. (C) Further heterogeneity at the cellular level is added by environmental factors. Proximity to blood vessels (vascular and hypoxic niches), paracrine signals between tumor cells, and immune responses (inflammatory niche), will influence individual tumor cell biology, including regulating stemness versus differentiation state of glioma stem cells (GSCs).