Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma

Abstract

The cellular origins and the mechanisms of progression, maintenance of tumorigenicity, and therapeutic resistance are central questions in the glioblastoma multiforme (GBM) field. Using tumor suppressor mouse models, our group recently reported two independent populations of adult GBM-initiating central nervous system progenitors. We found different functional and molecular subtypes depending on the tumor-initiating cell lineage, indicating that the cell of origin is a driver of GBM subtype diversity. Using an in vivo model, we also showed that GBM cancer stem cells (CSCs) or glioma stem cells (GSCs) contribute to resistance to chemotherapeutic agents and that genetic ablation of GSCs leads to a delay in tumor progression. These studies are consistent with the cell of origin and CSCs as critical regulators of the pathogenesis of GBM.

Figure 1

Two independent populations of glioblastoma multiforme (GBM)-initiating central nervous system (CNS) progenitors exist in the adult mouse brain. (Right) GBMs can be initiated by tumor suppressor mutations in adult neuronal progenitor cells (NPCs) and adult oligodendrocyte progenitor cells (OPCs), which give rise to histologically and molecularly distinct tumors. NPC-driven type 1 tumors are infiltrative gliomas mostly found in the dorsal brain, whereas OPC-driven type 2 tumors have more defined tumor borders prevalent in ventral brain regions. (Left) Lineage hierarchy of CNS cells: Multipotent CNS stem cells undergo asymmetric cell division to produce bipotential progenitor cells that give rise to lineage-restricted progenitors that differentiate into mature CNS cell types. Other potential unique subsets of adult progenitor lineages may give rise to additional GBM subtypes.

Figure 2

A restricted cell population in a spontaneous glioblastoma multiforme (GBM) mouse model is responsible for tumor recurrence after chemotherapy. (A) A cartoon depicts the heterogeneity of glioblastoma. Dark green cells represent the quiescent stem cells; yellow, red, and blue cells indicate the actively dividing cells with different proliferative potential; light green cells, which represent the bulk tumor cells, have exited the cell cycle. (B) Upon temozolomide (TMZ) treatment, most of the dividing cells are eradicated. (C) Quiescent stem-like cancer cells re-enter the cell cycle to repropagate the tumor. They can divide symmetrically to form more stem cells (self-renewal) or asymmetrically to generate more proliferative cells.