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Glioblastoma-derived tumorospheres
identify a population of tumor stem-like cells with angiogenic
potential and enhanced multidrug resistance phenotype
Andrea Salmaggi1*, Amerigo
Boiardi1, Maurizio Gelati1, Annamaria
Russo2, Chiara Calatozzolo1, Emilio
Ciusani1, Francesca Luisa Sciacca1,
Arianna Ottolina1, Eugenio Agostino Parati1,
Caterina La Porta3, Giulio Alessandri1,
Carlo Marras1, Danilo Croci1, Marco
De Rossi1
1Istituto
Nazionale Neurologico "Carlo Besta", Via Celoria 11, 20133
Milan, Italy. 2Central Hospital Sant'Anna, Via Napoleona
60, 22100 Como, Italy. 3Department of Biomolecular Science
and Biotechnology, Via Celoria 26, 20133 Milan, Italy -- *Correspondence
to Andrea Salmaggi, Istituto Nazionale Neurologico "Carlo Besta",
Via Celoria 11, 20133 Milan, Italy. Email: Andrea Salmaggi
(salmaggi@istituto-besta.it) -- Received: 1 June 2006; Accepted: 1
August 2006; Published Online: 15 Sep 2006
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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.
Keywords: brain tumor stem-like
cells, CXCL12, VEGF, MDR proteins and adhesion molecules
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