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.
Highlights
Glioblastoma (GB—grade IV glioma) is the most aggressive and common cancer of the central nervous system in adults, with over 10,000 new cases in the United States per year [1]
We investigated the protein disulfide-isomerase A3 (PDIA3) expression in the tumor and the nearby parenchyma from 18 GB patients and our data showed the expression of PDIA3 in tumor cells and in glioma-associated microglia/macrophages (GAMs), supporting its potential role in cellular and molecular processes related to GB
By comparing the effects of GB-derived Conditioned media (CM) on microglial cells, we found opposite effects: on the one hand, total signal transducer and activator of transcription 3 (STAT3) was upregulated when cells were treated with PDIA3-silenced basal conditioned media (B-CM); on the other hand, STAT3 was downregulated when cells were exposed to PDIA3-silenced Pre-stimulated conditioned media (PS-CM)
Summary
Glioblastoma (GB—grade IV glioma) is the most aggressive and common cancer of the central nervous system in adults, with over 10,000 new cases in the United States per year [1]. Due to its invasiveness and infiltrative behavior, GB is characterized by a median overall survival of only 14–16 months. This tumor still represents an unmet medical need and it is necessary to identify novel targets, both in the tumor and its microenvironment, to develop more effective and targeted therapies. The GB tumor microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that represent the largest population infiltrating the tumor [3]. GAMs possess different dynamic states of activation: the M1 state, which is tumor suppressive, and the M2 state, which is tumor supportive, contributing to tumor growth. It is known that, between GAMs and GB cells, there is a reciprocal interaction, the role of this cross-talk on GB progression is still poorly characterized
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