title: Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model.
abstract: Increasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme. CSCs are highly tumorigenic, capable of self-renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. To elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft glioblastoma recurrent models induced by anti-glioma chemotherapy, temozolomide. In this model, we observed a significant phenotypic shift towards an undifferentiated population. We confirmed these findings in vitro as sorted CD133-negative populations cultured in differentiation-forcing media were found to acquire CD133 expression following chemotherapy treatment. To investigate this phenotypic switch at the single-cell level, glioma stem cell (GSC)-specific promoter-based reporter systems were engineered to track changes in the GSC population in real time. We observed the active phenotypic and functional switch of single non-stem glioma cells to a stem-like state and that temozolomide therapy significantly increased the rate of single-cell conversions. Importantly, we showed the therapy-induced hypoxia-inducible factors (HIF) 1α and HIF2α play key roles in allowing non-stem glioma cells to acquire stem-like traits, as the expression of both HIFs increase upon temozolomide therapy and knockdown of HIFs expression inhibits the interconversion between non-stem glioma cells and GSCs post-therapy. On the basis of our results, we propose that anti-glioma chemotherapy promotes the accumulation of HIFs in the glioblastoma multiforme cells that induces the formation of therapy-resistant GSCs responsible for recurrence. Mol Cancer Ther; 15(12); 3064-76. ©2016 AACR.
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Gina
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Brenda
authors.initials: B
authors.lastname: Auffinger
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Donna
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Tanwir
authors.initials: T
authors.lastname: Hasan
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Marc
authors.initials: M
authors.lastname: Deheeger
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Alex L
authors.initials: AL
authors.lastname: Tobias
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Atashi
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. atique.ahmed@northwestern.edu.
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D017930:Genes, Reporter; D005910:Glioma / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit