Abstract
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.
Highlights
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults with short median survival (15 months) despite modern treatment: surgery followed by radio- and chemotherapy [26]
Results demonstrated a significant increase in B7-H3 in Subventricular Zone (SVZ)-GBM cells compared to tumor mass (TM)-GBM cells, which could be validated at protein and mRNA levels (Fig. 1b, c), confirming that B7-H3 is overexpressed in SVZ-GBM cells compared to TM-GBM cells
REMBRANDT, The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) database analysis revealed a higher level of mRNA coding for B7-H3 (CD276) in GBM compared to non-cancerous brain tissues or lower grades gliomas; oligodendroglioma, oligoastrocytoma and astrocytoma
Summary
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults with short median survival (15 months) despite modern treatment: surgery followed by radio- and chemotherapy [26]. This disastrous mean survival time is due to systematic GBM recurrence [39]. Current literature suggests a role for GBM stem cells (GSC) in GBM initiation, maintenance and resistance to therapy. This makes them potential cells of origin for GBM recurrence. SVZ-GBM cells express neural stem cell (NSC) markers and are more tumorigenic than TM-GBM cells
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