The potential origin of glioblastoma initiating cells

Abstract

Despite intensive clinical and laboratory research and effort, Glioblastoma remains the most common and invariably lethal primary cancer of the central nervous system. The identification of stem cell and lineage-restricted progenitor cell populations within the adult human brain in conjunction with the discovery of stem-like cells derived from gliomas which are themselves tumorigenic and have been shown to have properties of self-renewal and multipotency, has led to the hypothesis that this population of cells may represent glioma initiating cells. Extensive research characterizing the anatomic distribution and phenotype of neural stem cells in the adult brain, and the genetic underpinnings needed for malignant transformation may ultimately lead to the identification of the cellular origin for glioblastoma. Defining the cellular origin of this lethal disease may ultimately provide new therapeutic targets and modalities finally altering an otherwise bleak outcome for patients with glioblastoma.

Figure 1

Structure of the Rodent SVZ. (A) Drawing depicting the progression of neural stem cell (type B) to oligodendroglial precursors (OPC) or transit amplifying cells (type C) to immature neuroblasts (type A). (B) Drawing depicting the cytoarchitecture and cellular composition of the rodent SVZ. (C) Immunohistochemistry (40x) of the rodent SVZ. GFAP – glial fibrillary acidic protein; DCx – doublecortin; DAPI – 4′,6-diamidino-2-phenylindole; E—ependymal cells; A—type A cells; B—type B cells.

Figure 2

Structure of the Human SVZ. (A) Drawing depicting the cellular composition and cytoarchitecture of the human SVZ. Green cells represent layer III astrocytes, blue cells are a trapped ependymal cell rest, and elongated red cells are migratory neuron-like cells characterized at the layer III-IV interface (see text for more information). (B) Immunohistochemistry (20x) depicting the four layers that make up the human SVZ (Layer I – Ependymal layer, Layer II – Hypocellular gap, Layer III – Astrocytic ribbon, Layer IV – Transitional zone). GFAP – glial fibrillary acidic protein; DAPI – 4′,6-diamidino-2-phenylindole.

Figure 3

Differential oncologic effects upon cells of the human brain with varying proliferative potential. Left: T1-weighted coronal MRI of the human brain. Top right: Drawing depicting the putative effect of chemical and mutational insults experimentally proposed to be involved in glioblastoma formation upon SVZ derived cells with proliferative capacity. Bottom right: Drawing depicting the absent or reduced effect upon subcortical/cortical cells known to have decreased proliferative capacity compared with the SVZ of chemical and insults experimentally proposed to be involved in glioblastoma formation. ENU - N-ethyl-N-nitrosourea; EGF - epithelial derived growth factor; PDGF - platelet derived growth factor, NF – neurofibromatosis.