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Published on: November 28, 2015
PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation
Marta Chiavari1, Gabriella Maria Pia Ciotti1, Francesco Canonico2
1Dipartimento di Bioetica e Sicurezza, Sezione di Farmacologia-Catholic University Medical School, 00168 Rome, Italy.
Abstract:
The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the modulation of which has been reported in a variety of cancers. Moreover, by using The Cancer Genome Atlas database, we found that overexpression of PDIA3 correlated with about 55% reduction of overall survival of glioma patients. Therefore, we analyzed the expression of ERp57/PDIA3 using specimens obtained after surgery from 18 GB patients. Immunohistochemical analysis of tumor samples revealed ERp57/PDIA3 expression in GB cells as well as in GAMs. The ERp57/PDIA3 levels were higher in GAMs than in the microglia present in the surrounding parenchyma. Therefore, we studied the role of PDIA3 modulation in microglia-glioma interaction, based on the ability of conditioned media collected from human GB cells to induce the activation of microglial cells. The results indicated that reduced PDIA3 expression/activity in GB cells significantly limited the microglia pro-tumor polarization towards the M2 phenotype and the production of pro-inflammatory factors. Our data support a role of PDIA3 expression in GB-mediated protumor activation of microglia.
Insights
Endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3) is expressed in glioblastoma (GB) and glioma-associated microglia/macrophages (GAMs). Reduced PDIA3 in GB cells limits GAM pro-tumor polarization and inflammation.
Area of Science:
- Neuro-oncology
- Cancer Immunology
- Molecular Biology
Background:
- The glioblastoma (GB) microenvironment contains poorly characterized glioma-associated microglia/macrophages (GAMs).
- Endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3) is implicated in various cancers and its overexpression correlates with reduced glioma patient survival.
- ERp57/PDIA3's role in GAM regulation within the GB microenvironment is largely unknown.
Purpose of the Study:
- To investigate the expression and function of ERp57/PDIA3 in glioblastoma.
- To determine the role of ERp57/PDIA3 in the interaction between glioblastoma cells and microglia/macrophages.
- To assess the impact of PDIA3 modulation on microglia polarization and pro-tumor factor production.
Main Methods:
- Analysis of ERp57/PDIA3 expression in surgical specimens from 18 glioblastoma patients using immunohistochemistry.
- Comparison of ERp57/PDIA3 levels in GAMs versus surrounding parenchymal microglia.
- Assessment of microglia activation and polarization using conditioned media from glioblastoma cells with modulated PDIA3 expression.
Main Results:
- ERp57/PDIA3 was expressed in both glioblastoma cells and GAMs.
- ERp57/PDIA3 levels were significantly higher in GAMs compared to normal microglia.
- Reduced PDIA3 expression/activity in glioblastoma cells decreased M2 polarization of microglia and pro-inflammatory factor production.
Conclusions:
- ERp57/PDIA3 is present in glioblastoma cells and GAMs, with higher levels in GAMs.
- PDIA3 plays a role in glioblastoma-mediated pro-tumor activation of microglia.
- Targeting PDIA3 may represent a therapeutic strategy for glioblastoma by modulating the tumor immune microenvironment.
