title: Senescence from glioma stem cell differentiation promotes tumor growth.
abstract: Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins.
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan; Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ouchi
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Migita
authors.affiliation: Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan; Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address: hseimiya@jfcr.or.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*
chemical_list: D042501:Angiogenic Proteins
keywords: Angiogenesis; Cancer stem cell; Glioblastoma; Paracrine effect; Senescence