title: Quantification, self-renewal, and genetic tracing of FL1⁺ tumor-initiating cells in a large cohort of human gliomas.
abstract: Evidence has emerged that the initiation and growth of gliomas is sustained by a subpopulation of cancer-initiating cells (CICs). Because of the difficulty of using markers to tag CICs in gliomas, we have previously exploited more robust phenotypic characteristics, including a specific morphology and intrincic autofluorescence, to identify and isolate a subpopulation of glioma CICs, called FL1(+). The objective of this study was to further validate our method in a large cohort of human glioma and a mouse model of glioma. Seventy-four human gliomas of all grades and the GFAP-V(12)HA-ras B8 mouse model were analyzed for in vitro self-renewal capacity and their content of FL1(+). Nonneoplastic brain tissue and embryonic mouse brain were used as control. Genetic traceability along passages was assessed with microsatellite analysis. We found that FL1(+) cells from low-grade gliomas and from control nonneoplasic brain tissue show a lower level of autofluorescence and undergo a restricted number of cell divisions before dying in culture. In contrast, we found that FL1(+) cells derived from many but not all high-grade gliomas acquire high levels of autofluorescence and can be propagated in long-term cultures. Moreover, FL1(+) cells show a remarkable traceability over time in vitro and in vivo. Our results show that FL1(+) cells can be found in all specimens of a large cohort of human gliomas of different grades and in a model of genetically induced mouse glioma as well as nonneoplastic brain. However, their self-renewal capacity is variable and seems to be dependent on the tumor grade.
authors.affiliation: Department of Clinical Neurosciences, Service of Neurosurgery, Rue Gabrielle-Perret-Gentil, 4, CH-1211 Geneva, Switzerland. virginie.clement@unige.ch
authors.forename: Virginie
authors.initials: V
authors.lastname: Clément-Schatlo
authors.forename: Denis
authors.initials: D
authors.lastname: Marino
authors.forename: Karim
authors.initials: K
authors.lastname: Burkhardt
authors.forename: Patrick
authors.initials: P
authors.lastname: Teta
authors.forename: Fabienne
authors.initials: F
authors.lastname: Leyvraz
authors.forename: Bawarjan
authors.initials: B
authors.lastname: Schatlo
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Karl
authors.initials: K
authors.lastname: Schaller
authors.forename: Vincent
authors.initials: V
authors.lastname: Castella
authors.forename: Ivan
authors.initials: I
authors.lastname: Radovanovic
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D005453:Fluorescence; D011905:Genes, ras; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011379:Prognosis; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D005904:Glial Fibrillary Acidic Protein