[en] Short survival of glioblastoma (GBM) patients is due to systematic tumor recurrence. Our laboratory identified a GBM cell subpopulation able to leave the tumor mass (TM) and invade the subventricular zone (SVZ-GBM cells). SVZ-GBM cells escape treatment and appear to contribute to GBM recurrence. This study aims to identify proteins specifically expressed by SVZ-GBM cells and to define their role(s) in GBM aggressiveness and recurrence. The proteome was compared between GBM cells located in the initial TM and SVZ-GBM cells using mass spectrometry. Among differentially expressed proteins, we confirmed B7-H3 by western blot (WB) and quantitative RT-PCR. B7-H3 expression was compared by immunohistochemistry and WB (including expression of its isoforms) between human GBM (N = 14) and non-cancerous brain tissue (N = 8), as well as newly diagnosed GBM and patient-matched recurrences (N = 11). Finally, the expression of B7-H3 was modulated with short hairpin RNA and/or over-expression vectors to determine its functional role in GBM using in vitro assays and a xenograft mouse model of GBM. B7-H3 was a marker for SVZ-GBM cells. It was also increased in human GBM pericytes, myeloid cells and neoplastic cells. B7-H3 inhibition in GBM cells reduced their tumorigenicity. Out of the two B7-H3 isoforms, only 2IgB7-H3 was detected in non-cancerous brain tissue, whereas 4IgB7-H3 was specific for GBM. 2IgB7-H3 expression was higher in GBM recurrences and increased resistance to temozolomide-mediated apoptosis. To conclude, 4IgB7-H3 is an interesting candidate for GBM targeted therapies, while 2IgB7-H3 could be involved in recurrence through resistance to chemotherapy.
Disciplines :
Oncology
Author, co-author :
Di Gregorio, Marina ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
Coppieters't Wallant, Natacha ✱; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Nervous system disorders and therapy
LOMBARD, Arnaud ; Centre Hospitalier Universitaire de Liège - CHU > > Service de neurochirurgie
Lumapat, Paul Noel; Laboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences Research Centre, University of Liège, Avenue de L'Hôpital, 1, 4000, Liège, Belgium
Scholtes, Félix ✱; Centre Hospitalier Universitaire de Liège - CHU > > Service de neurochirurgie
Rogister, Bernard ✱; Centre Hospitalier Universitaire de Liège - CHU > > Service de neurologie
✱ These authors have contributed equally to this work.
Language :
English
Title :
The expression of B7-H3 isoforms in newly diagnosed glioblastoma and recurrence and their functional role.
Fonds Léon Fredericq [BE] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Neurological Foundation of New Zealand [NZ]
Funding text :
We would like to thank donors and their family for their generous gift of brain tissues. We also thank the Neurosurgical department of the academic hospital (CHU of Li?ge, Li?ge, Belgium), the Biobank of the Hospital and the University of Li?ge (BHUL, Uli?ge, Li?ge, Belgium), the GIGA proteomics, GIGA Immunohistology and GIGA Vector Viral Platforms for their expertise and technical assistance.
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