title: Conversion of glioma cells to glioma stem-like cells by angiocrine factors.
abstract: Glioma stem-like cells (GSCs) contribute to tumor initiation, progression, and therapeutic resistance, but their cellular origin remains largely unknown. Here, using a stem/progenitor cell-fate tracking reporter system in which eGFP is expressed by promoter of OCT4 that is activated in stem/progenitor cells, we demonstrate that eGFP-negative glioma cells (GCs) became eGFP-positive-GCs in both in vitro cultures and in vivo xenografts. These eGFP-positive-GCs exhibited GSC features and primarily localized to the perivascular region in tumor xenografts, similar to the existence of OCT4-expressing GCs in the perivascular region of human glioblastoma specimens. Angiocrine factors, including nitric oxide (NO), converted eGFP-negative-GCs into eGFP-positive-GCs. Mechanistically, NO signaling conferred GSC features to GCs by increasing OCT4 and NOTCH signaling via ID4. NO signaling blockade and a suicide gene induction prevented tumorigenicity with a decrease in eGFP-positive-GCs in the perivascular region. Taken together, our results reveal the molecular mechanism underlying GSCs generation by cancer cell dedifferentiation.
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Jun-Kyum
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Jeon
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Jeon
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Se-Yeong
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Xiong
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Animal Science, Chonnam National University, Gwangju 61185, Republic of Korea.
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, PR China.
authors.forename: Xun
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address: hg-kim@korea.ac.kr.
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic
chemical_list: D042501:Angiogenic Proteins; D036341:Intercellular Signaling Peptides and Proteins
keywords: Angiocrine factors; Glioma cells; Glioma stem-like cells; ID4; OCT4