A restricted cell population propagates glioblastoma growth after chemotherapy

J Chen, Y Li, TS Yu, RM McKay, DK Burns, SG Kernie… - Nature, 2012 - nature.com
J Chen, Y Li, TS Yu, RM McKay, DK Burns, SG Kernie, LF Parada
Nature, 2012nature.com
Glioblastoma multiforme is the most common primary malignant brain tumour, with a median
survival of about one year. This poor prognosis is due to therapeutic resistance and tumour
recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a
genetically engineered mouse model of glioma, here we identify a subset of endogenous
tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is
administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) …
Abstract
Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.
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