Involvement of hormones and their receptors in the progression of low-and high-grade glioma
Résumé
Introduction : Gliomas are the most common primary brain tumors in adults. The WHO classifies these tumors according to their degree of malignancy (histologicalgrade 1 to 4) and molecular subtype (IDH1 gene mutation, 1p19q codeletion):astrocytoma, oligodendroglioma and glioblastoma (IDHwt grade 4). Conventional treatment of glioblastoma consists in a concomitant radio-chemotherapy (temozolomide) and in some cases a chirurgical resection. Despite, the 5-yearsurvival rate is less than 5 %. Few risk factors are clearly defined, but womenare 1.5-fold less affected than men. Based on these observations, wehypothesized that hormonal and particularly estrogenic signaling have neuroprotective properties and addressed the key role of the g-protein coupled estrogen receptor GPER1.
Material and Methods : The association between patient survival and the expressions of GPER1 or its related genes was investigated through the mining of TCGA-LGG/GBM databasesand a workflow of statistical and bioinformatics analyses. The impact of GPERactivity on tumor growth was also explored in ex vivo cultured low- and high-grade patient samples and glioblastoma primary or established cell lines exposedto GPER1 agonist (G-1) and/or temozolomide and/or radiotherapy.
Results and Discussions : For the first time, we highlighted the association between a high GPER1 expression and patient survival and identified gender and tumor subtype specific related-gene signatures of good prognosis. Ex vivo, G-1 induced a significant decrease in glioblastoma cell proliferation. We observed a cell cycle arrest inG2/M phase caused by a disruption of the microtubular network. Finally, G-1potentiated the efficacy of standard treatment, even in chemotherapy less-sensitive cells, and could lead to cell apoptosis.
Conclusion : Taken together, our results supported the hormone-sensitivity of low- and high grade glioma and suggested that G-1, in combination with standard therapy,might be a promising way to limit the progression and aggressiveness of GBM.We also highlighted the need for a gender-specific approach to both investigatethe mechanisms that underly glioma progression and search for more efficient and tailored therapies of this still incurable disease.