Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 9, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-021-01167-w
Keywords
Glioblastoma; B7-H3; Isoforms; Recurrence
Categories
Funding
- National Fund for Scientific Research (F.N.R.S)
- Televie sub-organization
- Special Funds of the University of Liege
- Anti-Cancer Centre Foundation
- Leon Fredericq Foundation
- Neurological Foundation of New Zealand
- NanoFar (Erasmus Mundus, European doctorate in nanomedicine and pharmaceutical innovation)
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This study identified a subpopulation of GBM cells (SVZ-GBM cells) that have the ability to escape treatment and contribute to tumor recurrence. The protein B7-H3 was found to be specifically expressed by SVZ-GBM cells and may play a crucial role in GBM aggressiveness and recurrence.
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.
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