PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain.
Platelet-derived growth factor (PDGF) plays a major role in regulating migration, proliferation, and differentiation of glial progenitors during normal brain development and in the abnormal proliferation and dispersion that drives the formation of malignant gliomas. To further explore the relationship between PDGF's effects on normal glial progenitors and its role in the formation of gliomas, we infected progenitor cells in the subventricular zone (SVZ) of the lateral ventricle of neonatal rat pups with a retrovirus that expresses PDGF and green fluorescent protein (GFP). At 3 days post-injection (dpi), a proliferation of PDGFRalpha+ progenitors was seen in the SVZ and white matter around the injection site and by 10 dpi the animals had large diffusely infiltrating tumors that resembled glioblastomas. The tumors contained a massive proliferation of both infected and uninfected PDGFRalpha+ progenitors, suggesting that PDGF was driving tumor formation via both autocrine and paracrine signaling. Rats co-injected with two retroviruses (one that expresses PDGF-IRES-DSRED and one that expresses only GFP) formed tumors that contained a mixture of DSRED+ cells (PDGF producers) and GFP+ cells (recruited progenitors). Time-lapse microscopy of slice cultures confirmed that both DSRED+ and GFP+ cells were highly migratory and proliferative. Furthermore, adding exogenous PDGF to slice cultures generated from nontumor-bearing brains (injected with control GFP retrovirus only) stimulated the migration and proliferation of GFP+ progenitors. These findings reveal the inherent growth factor responsiveness and tumorigenic potential of PDGFRalpha+ progenitors and highlight the importance of paracrine signaling in stimulating glioma growth and infiltration.
Assanah
M C
MC
Department of Neurological Surgery, Columbia University, New York, New York 10032, USA.
Bruce
J N
JN
Suzuki
S O
SO
Chen
A
A
Goldman
J E
JE
Canoll
P
P
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020547:Lateral Ventricles / Q000378:metabolism / Q000502:physiology; D018613:Microscopy, Confocal; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009924:Organ Culture Techniques; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D013194:Staining and Labeling; D013234:Stem Cells / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D049452:Green Fluorescent Proteins