The developmental origin of brain tumours: a cellular and molecular framework

Abstract

The development of the nervous system relies on the coordinated regulation of stem cell self-renewal and differentiation. The discovery that brain tumours contain a subpopulation of cells with stem/progenitor characteristics that are capable of sustaining tumour growth has emphasized the importance of understanding the cellular dynamics and the molecular pathways regulating neural stem cell behaviour. By focusing on recent work on glioma and medulloblastoma, we review how lineage tracing contributed to dissecting the embryonic origin of brain tumours and how lineage-specific mechanisms that regulate stem cell behaviour in the embryo may be subverted in cancer to achieve uncontrolled proliferation and suppression of differentiation.

Fig. 1.

Cell of origin in medulloblastoma subgroups. (A) Posterolateral view of the mouse developing cerebellum. (B) Sagittal section of the developing cerebellum showing the location of the precursors that give rise to the distinct medulloblastoma subgroups shown in C. Sonic hedgehog-positive (SHH) medulloblastomas derive from GNPs in the EGL (blue), WNT-positive medulloblastomas derive from the lower RL and dorsal brain stem (yellow), group 3 medulloblastomas are thought to originate from either VZ or EGL progenitors overexpressing the oncogene Myc (grey) and group 4 medulloblastomas have been proposed to derive from cells with active LMX1A, TBR2 and LHX2 super-enhancers in the NTZ that contains deep nuclei originating from the upper RL (brown). Question marks under the cell of origin in groups 3 and 4 highlight the difficulty in pinpointing a specific cell of origin for these subgroups. Medulloblastoma classification is also constantly evolving and further subdivisions within these four subgroups have been recently reported (see Cavalli et al., 2017). EGL, external granule cell layer; GNPs, granule neuron precursors; lRL, lower rhombic lip; MB, medulloblastoma; NTZ, nuclear transitory zone; RP, roof plate; uRL, upper rhombic lip; VZ, ventricular zone.

Fig. 2.

Mechanisms of ‘stemness’ acquisition in cancer. (A) Under physiological conditions, multipotent neural stem cells (NSCs) self-renew and differentiate into fate-restricted progenitors, which are capable of lineage amplification and differentiation to the three main cell types in the brain: neurons (blue), astrocytes (orange) and oligodendrocytes (yellow). (B) Cancer cells can arise from de-regulation of NSC self-renewal (curved bold arrow, I), from de-differentiation of cells that revert back to a stem or progenitor-like state (dashed arrows, II) and/or from failed differentiation of stem (I) and progenitor (III) cells that are locked in a pro-proliferative state and differentiate aberrantly (curved bold arrows, I and III). APC, astrocytic progenitor cells; NPC, neural progenitor cells; OPC, oligodendrocyte precursor cells.