Panagopoulos Alexandros Theodoros, Gomes Renata Nascimento, Almeida Fernando Gonçalves, da Costa Souza Felipe, Veiga José Carlos Esteves, Nicolaou Anna, Colquhoun Alison
Department of Neurosurgery, Santa Casa Hospital, São Paulo, Brazil.
Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.
Prostaglandins Other Lipid Mediat. 2018 Jul;137:52-62. doi: 10.1016/j.prostaglandins.2018.06.003. Epub 2018 Jun 30.
Prostanoids derived from the activity of cyclooxygenases and their respective synthases contribute to both active inflammation and immune response in the tumor microenvironment. Their synthesis, deactivation and role in glioma biology have not yet been fully explored and require further study. Using quantitative real time PCR, gas chromatography/ electron impact mass spectrometry and liquid chromatography/ electrospray ionization tandem mass spectrometry, we have further characterized the prostanoid pathway in grade IV glioblastoma (GBM). We observed significant correlations between high mRNA expression levels and poor patient survival for microsomal PGE synthase 1 (mPGES1) and prostaglandin reductase 1 (PTGR1). Conversely, high mRNA expression levels for 15-hydroxyprostaglandin dehydrogenase (15-HPGD) were correlated with better patient survival. GBMs had a higher quantity of the prostanoid precursor, arachidonic acid, versus grade II/III tumors and in GBMs a significant positive correlation was found between arachidonic acid and PGE content. GBMs also had higher concentrations of TXB, PGD, PGE and PGF versus grade II/III tumors. A significant decrease in survival was detected for high versus low PGE, PGE + PGE deactivation products (PGEMs) and PGF in GBM patients. Our data show the potential importance of prostanoid metabolism in the progression towards GBM and provide evidence that higher PGE and PGF concentrations in the tumor are correlated with poorer patient survival. Our findings highlight the potential importance of the enzymes 15-HPGD and PTGR1 as prognostic biomarkers which could be used to predict survival outcome of patients with GBM.
由环氧化酶及其各自合酶的活性产生的前列腺素类物质在肿瘤微环境中对活跃的炎症和免疫反应均有作用。它们在神经胶质瘤生物学中的合成、失活及作用尚未得到充分研究,需要进一步探讨。我们运用定量实时聚合酶链反应、气相色谱/电子轰击质谱法以及液相色谱/电喷雾电离串联质谱法,进一步对IV级胶质母细胞瘤(GBM)中的前列腺素类物质途径进行了特征分析。我们观察到微粒体前列腺素E合酶1(mPGES1)和前列腺素还原酶1(PTGR1)的高信使核糖核酸(mRNA)表达水平与患者较差的生存率之间存在显著相关性。相反,15-羟基前列腺素脱氢酶(15-HPGD)的高mRNA表达水平与患者较好的生存率相关。与II/III级肿瘤相比,GBM中前列腺素类物质前体花生四烯酸的含量更高,并且在GBM中,花生四烯酸与前列腺素E含量之间存在显著正相关。与II/III级肿瘤相比,GBM中血栓素B2(TXB)、前列腺素D2(PGD)、前列腺素E2(PGE)和前列腺素F2α(PGF)的浓度也更高。在GBM患者中,高PGE、PGE + PGE失活产物(PGEMs)和PGF水平的患者生存率显著降低。我们的数据表明前列腺素类物质代谢在向GBM进展过程中的潜在重要性,并提供证据表明肿瘤中较高的PGE和PGF浓度与患者较差的生存率相关。我们的研究结果突出了15-HPGD和PTGR1作为预后生物标志物的潜在重要性,可用于预测GBM患者的生存结果。