title: Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy.
abstract: Glioblastoma multiforme patients have a poor prognosis due to therapeutic resistance and tumor relapse. It has been suggested that gliomas are driven by a rare subset of tumor cells known as glioma stem cells (GSCs). This hypothesis states that only a few GSCs are able to divide, differentiate, and initiate a new tumor. It has also been shown that this subpopulation is more resistant to conventional therapies than its differentiated counterpart. In order to understand glioma recurrence post therapy, we investigated the behavior of GSCs after primary chemotherapy. We first show that exposure of patient-derived as well as established glioma cell lines to therapeutic doses of temozolomide (TMZ), the most commonly used antiglioma chemotherapy, consistently increases the GSC pool over time both in vitro and in vivo. Secondly, lineage-tracing analysis of the expanded GSC pool suggests that such amplification is a result of a phenotypic shift in the non-GSC population to a GSC-like state in the presence of TMZ. The newly converted GSC population expresses markers associated with pluripotency and stemness, such as CD133, SOX2, Oct4, and Nestin. Furthermore, we show that intracranial implantation of the newly converted GSCs in nude mice results in a more efficient grafting and invasive phenotype. Taken together, these findings provide the first evidence that glioma cells exposed to chemotherapeutic agents are able to interconvert between non-GSCs and GSCs, thereby replenishing the original tumor population, leading to a more infiltrative phenotype and enhanced chemoresistance. This may represent a potential mechanism for therapeutic relapse.
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Auffinger
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Tobias
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lee
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Guo
authors.affiliation: The Brain Tumor Center, The University of Chicago, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dey
authors.affiliation: 1] The Brain Tumor Center, The University of Chicago, Chicago, IL, USA [2] Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Lesniak
authors.affiliation: 1] The Brain Tumor Center, The University of Chicago, Chicago, IL, USA [2] Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: A U
authors.initials: AU
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010641:Phenotype; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D018906:Antineoplastic Agents, Alkylating; D051792:Basic Helix-Loop-Helix Proteins; D003606:Dacarbazine; D000077204:Temozolomide; D000099162:Endothelial PAS Domain-Containing Protein 1