title: CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells.
abstract: CD133 is a cell surface marker expressed on progenitors of haematopoietic and endothelial cell lineages. Moreover, several studies have identified CD133 as a marker of brain tumor-initiating cells. In this study, human glioblastoma multiforme biopsies were engrafted intracerebrally into nude rats. The resulting tumors were serially passaged in vivo, and monitored by magnetic resonance imaging. CD133 expression was analyzed at various passages. Tumors initiated directly from the biopsies expressed little or no CD133, and showed no contrast enhancement suggesting an intact blood-brain barrier. During passaging, the tumors gradually displayed more contrast enhancement, increased angiogenesis and a shorter survival. Real-time qPCR and immunoblots showed that this was accompanied by increased CD133 expression. Primary biopsy spheroids and xenograft tumors were subsequently dissociated and flow sorted into CD133 negative and CD133 positive cell populations. Both populations incorporated BrdU in cell culture, and expressed the neural precursor marker nestin. Notably, CD133 negative cells derived from 6 different patients were tumorgenic when implanted into the rat brains. For 3 of these patients, analysis showed that the resulting tumors contained CD133 positive cells. In conclusion, we show that CD133 negative glioma cells are tumorgenic in nude rats, and that CD133 positive cells can be obtained from these tumors. Upon passaging of the tumors in vivo, CD133 expression is upregulated, coinciding with the onset of angiogenesis and a shorter survival. Thus, our findings do not suggest that CD133 expression is required for brain tumor initiation, but that it may be involved during brain tumor progression.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Per Ø
authors.initials: PØ
authors.lastname: Sakariassen
authors.forename: Oleg
authors.initials: O
authors.lastname: Tsinkalovsky
authors.forename: Heike
authors.initials: H
authors.lastname: Immervoll
authors.forename: Stig Ove
authors.initials: SO
authors.lastname: Bøe
authors.forename: Agnete
authors.initials: A
authors.lastname: Svendsen
authors.forename: Lars
authors.initials: L
authors.lastname: Prestegarden
authors.forename: Gro
authors.initials: G
authors.lastname: Røsland
authors.forename: Frits
authors.initials: F
authors.lastname: Thorsen
authors.forename: Linda
authors.initials: L
authors.lastname: Stuhr
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Per Ø
authors.initials: PØ
authors.lastname: Enger
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D005434:Flow Cytometry; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606025:Prom1 protein, rat; D012333:RNA, Messenger