ABSTRACT
BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumor that affects men more often than women. In addition, the former shows a poorer survival prognosis. To date, the reason for this sex-specific aggressiveness remains unclear. Therefore, the aim of this study is to investigate tumor processes that explain these sex differences. METHODS: This was a retrospective study of GBM patients which was stratified according to sex. A cohort with 73 tumors was analyzed with immunohistochemistry, RNA-seq and RT-qPCR to characterize differences in vascular and immunological profiles. Transcriptomic profiling, gene set enrichment analysis, and pathway enrichment analysis were used for discovering molecular pathways predominant in each group. We further investigated the therapeutic effect of bevacizumab (vascular endothelial growth factor A (VEGFA) blocking antibody) in a retrospective GBM cohort (36 tumors) based on sex differences. RESULTS: We found that under hypoxic tumor conditions, 2 distinct tumor immuno-angiogenic ecosystems develop linked to sex differences and ESR1 expression is generated. One of these subgroups, which includes male patients with low ESR1 expression, is characterized by vascular fragility associated with the appearance of regions of necrosis and high inflammation (called necroinflamed tumors). This male-specific tumor subtype shows high inflammation related to myeloid-derived suppressor cells infiltration. Using this stratification, we identified a possible group of patients who could respond to bevacizumab (BVZ) and revealed a genetic signature that may find clinical applications as a predictor of those who may benefit most from this treatment. CONCLUSIONS: This study provides a stratification based on the sexual differences in GBM, which associates the poor prognosis with the presence of immunosuppressive myeloid cells in the necrotic areas. This new stratification could change the current prognosis of GBM and identifies those who respond to BVZ treatment.
Subject(s)
Bevacizumab , Brain Neoplasms , Glioblastoma , Necrosis , Humans , Bevacizumab/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioblastoma/metabolism , Male , Female , Retrospective Studies , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Prognosis , Middle Aged , Antineoplastic Agents, Immunological/therapeutic use , Inflammation/pathology , Inflammation/drug therapy , Aged , Adult , Angiogenesis Inhibitors/therapeutic use , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Follow-Up Studies , Sex Characteristics , Survival RateABSTRACT
There is a bidirectional transplacental cell trafficking between mother and fetus during pregnancy in placental mammals. The presence and persistence of fetal cells in maternal tissues are known as fetal microchimerism (FMc). FMc has high multilineage potential with a great ability to differentiate and functionally integrate into maternal tissue. FMc has been found in various maternal tissues in animal models and humans. Its permanence in the maternal body up to decades after delivery suggests it might play an essential role in maternal pathophysiology. Studying the presence, localization, and characteristics of FMc in maternal tissues is key to understanding its impact on the woman's body. Here we comprehensively review the existence of FMc in different species and organs and tissues, aiming to better characterize their possible role in human health and disease. We also highlight several methodological considerations that would optimize the detection, quantification, and functional determination of FMc.
