Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma

Ahlame Saidi, Sophie Javerzat, Akeila Bellahcène, John De Vos, Lorenzo Bello, Vincent Castronovo, Manuel Deprez, Hugues Loiseau, Andreas Bikfalvi, Martin Hagedorn

Research output: Contribution to journalArticlepeer-review

Abstract

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 Affymetrix™ Gene-Chips. 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.

Original languageEnglish
Pages (from-to)2187-2198
Number of pages12
JournalInternational Journal of Cancer
Volume122
Issue number10
DOIs
Publication statusPublished - May 15 2008

Keywords

  • Anti-angiogenesis
  • Elafin
  • Glioblastoma
  • Microarray
  • YKL-40

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma'. Together they form a unique fingerprint.

Cite this