title: The evidence of glioblastoma heterogeneity.
abstract: Cancers are composed of heterogeneous combinations of cells that exhibit distinct phenotypic characteristics and proliferative potentials. Because most cancers have a clonal origin, cancer stem cells (CSCs) must generate phenotypically diverse progenies including mature CSCs that can self-renew indefinitely and differentiated cancer cells that possess limited proliferative potential. However, no convincing evidence exists to suggest that only single CSCs are representative of patients' tumors. To investigate the CSCs' diversity, we established 4 subclones from a glioblastoma patient. These subclones were subsequently propagated and analyzed. The morphology, the self-renewal and proliferative capacities of the subclones differed. Fluorescence-activated cell sorting and cDNA-microarray analyses revealed that each subclone was composed of distinct populations of cells. Moreover, the sensitivities of the subclones to an inhibitor of epidermal growth factor receptor were dissimilar. In a mouse model featuring xenografts of the subclones, the progression and invasion of tumors and animal survival were also different. Here, we present clear evidence that a brain tumor contains heterogeneous subclones that exhibit dissimilar morphologies and self-renewal and proliferative capacities. Our results suggest that single cell-derived subclones from a patient can produce phenotypically heterogeneous self-renewing progenies in both in vitro and in vivo settings.
authors.affiliation: Department of Neurosurgery, Gifu University School of Medicine, Gifu City, Gifu, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Soeda
authors.affiliation: Department of Tumor Pathology, Gifu University School of Medicine, Gifu City, Gifu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Department of Tissue and Organ Regeneration, Gifu University School of Medicine, Gifu City, Gifu, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.affiliation: Department of Neurosurgery, Gifu University School of Medicine, Gifu City, Gifu, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Yoshimura
authors.affiliation: Department of Neurosurgery, Gifu University School of Medicine, Gifu City, Gifu, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Iwama
authors.affiliation: Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Deric M
authors.initials: DM
authors.lastname: Park
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology*; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D011799:Quinazolines / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D018969:Insulin-Like Growth Factor Binding Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C102529:insulin-like growth factor binding protein-related protein 1; D066246:ErbB Receptors; D000077156:Gefitinib