Tumor progression and oncogene addiction in a PDGF-B-induced model of gliomagenesis.
Platelet-derived growth factor B (PDGF-B) overexpression induces gliomas of different grades from murine embryonic neural progenitors. For the first time, we formally demonstrated that PDGF-B-induced neoplasms undergo progression from nontumorigenic low-grade tumors toward highly malignant forms. This result, showing that PDGF-B signaling alone is insufficient to confer malignancy to cells, entails the requirement for further molecular lesions in this process. Our results indicate that one of these lesions is represented by the down-regulation of the oncosuppressor Btg2. By in vivo transplantation assays, we further demonstrate that fully progressed tumors are PDGF-B-addicted because their tumor-propagating ability is lost when the PDGF-B transgene is silenced, whereas it is promptly reacquired after its reactivation. We provide evidence that this oncogene addiction is not caused by the need for PDGF-B as a mitogen but, rather, to the fact that PDGF-B is required to overcome cell-cell contact inhibition and to confer in vivo infiltrating potential on tumor cells.
Calzolari
Filippo
F
National Institute for Cancer Research (IST), IRCCS, Genoa, Italy.
Appolloni
Irene
I
Tutucci
Evelina
E
Caviglia
Sara
S
Terrile
Marta
M
Corte
Giorgio
G
Malatesta
Paolo
P
D000818:Animals; D001921:Brain / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000473:pathology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009837:Oligodendroglioma / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
C489435:Btg2 protein, mouse; D017874:Immediate-Early Proteins; D020574:Proto-Oncogene Proteins c-sis; D025521:Tumor Suppressor Proteins