Abstract
Simple SummaryGlioblastoma is the most lethal tumor among all cancers with a median overall survival of 14 months and to develop new effective therapies is an urgent issue. Boron Neutron Capture Therapy (BNCT) is a unique radiation therapy that uses boron compounds and thermal neutrons. This study is aimed to investigate whether glioma stem cells, which is resistant to chemo-radiation therapy, take up a boron compound, p-boronophenylalanine (BPA) or not. Both in vitro and in vivo studies, more glioma stem like cells took up BPA compared with the differentiated glioma cells and indicated that BNCT can target to kill GSCs and be an effective therapy for malignant glioma.As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5–9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2–4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT.
Highlights
Glioblastoma (GBM) is the most lethal primary brain tumor, with a median overall survival of14 months
We found that even patients with recurrent gliomas, including those with poor prognosis, non-GBM patients with a Karnofsky performance score of less than 80 and GBM patients over 50 years of age with corticosteroid use, had a median survival time of 9.1 months after boron neutron capture therapy (BNCT) [6] compared with 4.4 months for patients with same prognostic factors within the New Approaches to Brain Tumor Therapy Central Nervous System (CNS) Consortium who were in other phase I/II trials for systemic or local therapy for recurrent glioma [2]
The differentiation markers glial fibrillary acidic protein (GFAP) and Tuj1 were expressed at higher levels in differentiated cells compared with glioma stem-like cells (GSLCs) (Figure 1a, b)
Summary
Glioblastoma (GBM) is the most lethal primary brain tumor, with a median overall survival of14 months. We have used boron neutron capture therapy (BNCT) to treat recurrent or newly. Using BNCT, we achieved better local control and survival benefit in patients with malignant glioma compared with the control cohort. We found that even patients with recurrent gliomas, including those with poor prognosis, non-GBM patients with a Karnofsky performance score of less than 80 and GBM patients over 50 years of age with corticosteroid use, had a median survival time of 9.1 months after BNCT [6] compared with 4.4 months for patients with same prognostic factors within the New Approaches to Brain Tumor Therapy Central Nervous System (CNS) Consortium who were in other phase I/II trials for systemic or local therapy for recurrent glioma [2]. Even after tumor-selective BNCT, recurrence was inevitable, the most frequent cause of death was cerebrospinal fluid (CSF) dissemination [2,7]
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