title: Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression.
abstract: The identity of the cells that contribute to brain tumor structure and progression remains unclear. Mesenchymal stem cells (MSCs) have recently been isolated from normal mouse brain. Here, we report the infiltration of MSC-like cells into the GL261 murine glioma model. These brain tumor-derived mesenchymal stem cells (BT-MSCs) are defined with the phenotype (Lin-Sca-1+CD9+CD44+CD166+/-) and have multipotent differentiation capacity. We show that the infiltration of BT-MSCs correlates to tumor progression; furthermore, BT-MSCs increased the proliferation rate of GL261 cells in vitro. For the first time, we report that the majority of GL261 cells expressed mesenchymal phenotype under both adherent and sphere culture conditions in vitro and that the non-MSC population is nontumorigenic in vivo. Although the GL261 cell line expressed mesenchymal phenotype markers in vitro, most BT-MSCs are recruited cells from host origin in both wild-type GL261 inoculated into green fluorescent protein (GFP)-transgenic mice and GL261-GFP cells inoculated into wild-type mice. We show the expression of chemokine receptors CXCR4 and CXCR6 on different recruited cell populations. In vivo, the GL261 cells change marker profile and acquire a phenotype that is more similar to cells growing in sphere culture conditions. Finally, we identify a BT-MSC population in human glioblastoma that is CD44+CD9+CD166+ both in freshly isolated and culture-expanded cells. Our data indicate that cells with MSC-like phenotype infiltrate into the tumor stroma and play an important role in tumor cell growth in vitro and in vivo. Thus, we suggest that targeting BT-MSCs could be a possible strategy for treating glioblastoma patients.
authors.affiliation: Vilhelm Magnus Laboratory, Institute for Surgical Research, CAST-Cancer Stem Cell Innovation Center and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway; Glioma Immunotherapy Group, Institute for Clinical Sciences, Department of Neurosurgery, Lund University, Lund, Sweden.
authors.forename: Jinan
authors.initials: J
authors.lastname: Behnan
authors.forename: Pauline
authors.initials: P
authors.lastname: Isakson
authors.forename: Mrinal
authors.initials: M
authors.lastname: Joel
authors.forename: Corrado
authors.initials: C
authors.lastname: Cilio
authors.forename: Iver A
authors.initials: IA
authors.lastname: Langmoen
authors.forename: Einar O
authors.initials: EO
authors.lastname: Vik-Mo
authors.forename: Wiaam
authors.initials: W
authors.lastname: Badn
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018450:Disease Progression; D005434:Flow Cytometry; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D016130:Immunophenotyping; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology; D054387:Receptors, CXCR / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D000075744:Receptors, CXCR6; D016019:Survival Analysis; D060245:Tetraspanin 29 / Q000378:metabolism
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; C514936:CXCR4 protein, mouse; C482906:Cxcr6 protein, mouse; D018960:Hyaluronan Receptors; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D000075744:Receptors, CXCR6; D060245:Tetraspanin 29; D049452:Green Fluorescent Proteins
keywords: Cell adhesion molecules; Cell biology; Cell culture; Cell migration; Cell surface markers; Glioma; Mesenchymal stem cells; Multipotential differentiation; Recruited cells