RESUMO
BACKGROUND: Imagining ways to prevent or treat glioblastoma (GBM) has been hindered by a lack of understanding of its pathogenesis. Although overexpression of platelet derived growth factor with two A-chains (PDGF-AA) may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture. Here we report a model that overcomes this barrier to authenticity. METHODS: Using a method developed to establish neural stem cell cultures, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, one of the putative cells of origin of GBM. We microdissected SVZ tissue from p53-null and wild-type adult mice, cultured cells in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumorigenicity. RESULTS: Counterintuitive to its canonical role as a growth factor, we observed abrupt and massive cell death in PDGF-AA: wild-type cells did not survive, whereas a small fraction of null cells evaded apoptosis. Surviving null cells displayed attenuated proliferation accompanied by whole chromosome gains and losses. After approximately 100 days in PDGF-AA, cells suddenly proliferated rapidly, acquired growth factor independence, and became tumorigenic in immune-competent mice. Transformed cells had an oligodendrocyte precursor-like lineage marker profile, were resistant to platelet derived growth factor receptor alpha inhibition, and harbored highly abnormal karyotypes similar to human GBM. CONCLUSION: This model associates genome instability in neural progenitor cells with chronic exposure to PDGF-AA and is the first to approximate the genomic landscape of human GBM and the first in which the earliest phases of the disease can be studied directly.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Células-Tronco Neurais , Fator de Crescimento Derivado de Plaquetas , Proteína Supressora de Tumor p53 , Animais , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Células Cultivadas , Glioblastoma/induzido quimicamente , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/metabolismoRESUMO
Oligodendroglioma is characterized by mutations of IDH and CIC, 1p/19q loss, and slow growth. We found that NHE-1 on 1p is silenced in oligodendrogliomas secondary to IDH-associated hypermethylation and 1p allelic loss. Silencing lowers intracellular pH and attenuates acid load recovery in oligodendroglioma cells. Others have shown that rapid tumor growth cannot occur without NHE-1-mediated neutralization of the acidosis generated by the Warburg glycolytic shift. Our findings show for the first time that the pH regulator NHE-1 can be silenced in a human cancer and also suggest that pH deregulation may contribute to the distinctive biology of human oligodendroglioma.