title: A restricted cell population propagates glioblastoma growth after chemotherapy.
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.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Li
authors.forename: Tzong-Shiue
authors.initials: TS
authors.lastname: Yu
authors.forename: Renée M
authors.initials: RM
authors.lastname: McKay
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D058948:Cell Tracking; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology; D000077204:Temozolomide; D019076:Transgenes / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D049452:Green Fluorescent Proteins; D003606:Dacarbazine; D015774:Ganciclovir; D000077204:Temozolomide