Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype.
We investigated in vitro the properties of selected populations of cancer stem-like cells defined as tumorospheres that were obtained from human glioblastoma. We also assessed their potential and capability of differentiating into mature cells of the central nervous system. In vivo, their tumorigenicity was confirmed after transplantation into the brain of non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice. The angiogenic potential of tumorospheres and glioblastoma-derived cells grown as adherent cells was revealed by evaluating the release of angiogenic factors such as vascular endothelial growth factor and CXCL12 by ELISA, as well as by rat aortic ring assay. The proliferative response of tumorospheres in the presence of CXCL12 was observed for the first time. Multidrug resistance-associated proteins 1 and 3 as well as other molecules conferring multidrug resistance were higher when compared with primary adherent cells derived from the same tumor. Finally, we obtained cells from the tumor developing after grafting that clearly expressed the putative neural stem cell marker CD133 as shown by FACS analysis and also nestin and CXCR4. The cells' positivity for glial fibrillary acidic protein was very low. Moreover these cells preserved their angiogenic potential. We conclude that human glioblastoma could contain tumor cell subsets with angiogenic and chemoresistance properties and that this chemoresistance potential is highly preserved by immature cells whereas the angiogenic potential is, to a higher extent, a property of mature cells. A better understanding of the features of these cell subsets may favor the development of more specifically targeted therapies.
Salmaggi
Andrea
A
Istituto Nazionale Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy. salmaggi@istituto-besta.it
Boiardi
Amerigo
A
Gelati
Maurizio
M
Russo
Annamaria
A
Calatozzolo
Chiara
C
Ciusani
Emilio
E
Sciacca
Francesca Luisa
FL
Ottolina
Arianna
A
Parati
Eugenio Agostino
EA
La Porta
Caterina
C
Alessandri
Giulio
G
Marras
Carlo
C
Croci
Danilo
D
De Rossi
Marco
M
D000071916:AC133 Antigen; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000293:Adolescent; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D010455:Peptides / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000071916:AC133 Antigen; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; C515255:CXCL12 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D006023:Glycoproteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C000606025:Prom1 protein, rat; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A