Article (Scientific journals)
Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma.
Saidi, Ahlame; Javerzat, Sophie; Bellahcene, Akeila et al.
2008In International Journal of Cancer, 122 (10), p. 2187-98
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Keywords :
Adult; Astrocytoma/blood supply/metabolism/mortality; Brain/metabolism/pathology; Brain Neoplasms/blood supply/metabolism/mortality; Cell Proliferation; Elafin/metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma/blood supply/metabolism/mortality; Glycoproteins/metabolism; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; RNA, Messenger/genetics/metabolism; RNA, Small Interfering/pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate; Tumor Markers, Biological/genetics/metabolism; Up-Regulation; Vascular Endothelial Growth Factor A/antagonists & inhibitors/genetics/metabolism
Abstract :
[en] Vascular endothelial growth factor (VEGF) inhibitors are the most promising anti-angiogenic agents used increasingly in the clinic. However, to be efficient, anti-VEGF agents need to be associated with classic chemotherapy. Exploring gene regulation in tumor cells during anti-angiogenesis might help to comprehend the molecular basis of response to treatment. To generate a defined anti-angiogenic condition in vivo, we transfected human glioma cells with short-interfering RNAs against VEGF-A and implanted them on the chick chorio-allantoic membrane. Gene regulation in avascular tumors was studied using human Affymetrixtrade mark GeneChips. Potentially important genes were further studied in glioma patients. Despite strong VEGF inhibition, we observed recurrent formation of small, avascular tumors. CHI3L2, IL1B, PI3/elafin and CHI3L1, which encodes for YKL-40, a putative prognosticator for various diseases, including cancer, were strongly up-regulated in avascular glioma. In glioblastoma patients, these genes showed coregulation and their expression differed significantly from low-grade glioma. Importantly, high levels of CHI3L1 (p = 0.036) and PI3/elafin mRNA (p = 0.0004) were significantly correlated with poor survival. Cox regression analysis further confirmed that PI3 and CHI3L1 levels are survival markers independent from patient age and sex. Elafin-positive tumor cells were only found in glioblastoma, where they were clustered around necrotic areas. PI3/elafin is strongly induced by serum deprivation and hypoxia in U87 glioma cells in vitro. Our results indicate that anti-angiogenesis in experimental glioma drives expression of critical genes which relate to disease aggressiveness in glioblastoma patients. In particular, CHI3L1 and PI3/elafin may be useful as new prognostic markers and new therapeutic targets.
Research center :
Giga-Cancer - ULiège
Disciplines :
Oncology
Biochemistry, biophysics & molecular biology
Author, co-author :
Saidi, Ahlame
Javerzat, Sophie
Bellahcene, Akeila ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
De Vos, John
Bello, Lorenzo
Castronovo, Vincenzo ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire - GIGA-R : Labo de recherche sur les métastases
Deprez, Manuel ;  Université de Liège - ULiège > Département des sciences cliniques > Neuropathologie
Loiseau, Hugues
Bikfalvi, Andreas
Hagedorn, Martin
Language :
English
Title :
Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma.
Publication date :
2008
Journal title :
International Journal of Cancer
ISSN :
0020-7136
eISSN :
1097-0215
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
122
Issue :
10
Pages :
2187-98
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
European Commission (STROMA)
La Ligue contre le Cancer
Comité de la Dordogne
ANR - Agence Nationale de la Recherche [FR]
Available on ORBi :
since 28 September 2009

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