Recent insights into PDGF-induced gliomagenesis

Abstract

Gliomas are aggressive and almost incurable glial brain tumors which frequently display abnormal platelet-derived growth factor (PDGF) signaling. Evidence gained from studies on several in vivo animal models has firmly established a causal connection between aberrant PDGF signaling and the formation of some gliomas. However, only recently has significant knowledge been gained regarding crucial issues such as the glioma cell of origin and the relationship between the transforming stimulus and the cellular characteristics of the resulting tumor. Based on recent evidence, we propose that PDGF can bias cell-fate decisions, driving the acquisition of cell type-specific features by the progeny of multipotent neural progenitors, thus determining the shape and direction of the transformation path. Furthermore, recent data about the cellular mechanisms of PDGF-driven glioma progression and maintenance indicate that PDGF may be required, unexpectedly, to override cell contact inhibition and promote glioma cell infiltration rather than to stimulate cell proliferation.

Figure 1

Platelet‐derived growth factor (PDGF) ligands and receptors and their effects on the glial lineage. A. Known members of the PDGF families of ligands and receptors; arrows indicate their known in vitro dimerization properties and their interaction with receptors. B. PDGF can induce neural progenitor cells (NPCs) to acquire an oligodendrocyte progenitor cell (OPC) identity. C. PDGF exerts its effects on OPC migration and proliferation by activating different signaling pathways in a concentration‐dependent manner. D. Neuronal and oligodendroglial generation by subventricular zone (SVZ) neural stem cells are regulated by PDGF signaling. CC = corpus callosum; LV = lateral ventricle; OB = olfactory bulb; PDGFR = platelet‐derived growth factor receptor; PI3K = phosphatidylinositol 3‐kinase; PLCγ = phospholipase‐C gamma. References are present for data summarized in B, C and D. The figure was drawn on the bases of the data contained in the cited papers and represents an original artwork.

Figure 2

Summary of in vivo models of platelet‐derived growth factor (PDGF)‐induced gliomagenesis; their basic experimental settings, targeted cell populations and tumorigenic effects. A. PDGF‐B transduction of neonatal neural precursors using the RCAS‐tva avian retroviral system. B. PDGF‐B/GFP transduction of adult white matter progenitors (upper cartoon) and continuous PDGF‐A intraventricular perfusion of the adult brain (lower cartoon). C. In utero transduction of telencephalic neural progenitors with PDGF‐B/GFP retroviral vectors. References are present for each model. The figure was drawn on the bases of the data contained in the cited papers and represents an original artwork. GFP = green fluorescent protein; RCAS = Replication‐Competent ASLV long terminal repeat with a Splice acceptor; SVZ = subventricular zone.

Figure 3

Platelet‐derived growth factor (PDGF)‐B induced gliomas only gradually acquire a fully malignant phenotype. Glioma can be observed in an in vivo model of gliomagenesis induced by the embryonic transduction of neural progenitors with PDGF‐B retroviruses. Experimental setting and survival curve show two main tumor groups that can be distinguished based on symptom onset and tumor‐propagating potential. The figure was drawn on the bases of the data contained in the cited papers and represents an original artwork. GFP = green fluorescent protein.

Figure 4

Resident glial progenitors are recruited to the tumor mass and contribute to the growth of platelet‐derived growth factor (PDGF)‐induced gliomas without achieving an autonomous tumorigenic potential, as revealed by reinjection experiments following dissociation. The figure was drawn on the bases of the data contained in the cited papers and represents an original artwork. FAC‐sorting = fluorescence‐activated cell‐sorting; GFP = green fluorescent protein.