包含WHO3级和4级的高级别神经胶质瘤(HGG)具有在过去十年中没有改善的差的总生存期(OS)。在这里,鉴定了代表肿瘤微环境(TME)四个组成部分的标志物,以定义它们在TME中的连锁表达并预测HGG的预后,即,白细胞介素6(IL6,炎症),诱导型一氧化氮合酶(iNOS),热休克蛋白70(HSP70,缺氧),血管内皮生长受体(VEGF),和内皮素1(ET1)(血管生成)和基质金属蛋白酶14(MMP14)和细胞间粘附分子1(ICAM1,细胞外基质)。建立用于HGG精确预测的非侵入性生物标志物组。对86例未经治疗的HGG患者和45例对照进行了定义的分析。细胞外/分泌性生物标志物的系统表达筛选点免疫测定(DIA),通过ELISA定量,并通过免疫细胞化学(ICC)验证。iNOS的表达,HSP70,IL-6,VEGF,发现ET1、MMP14和ICAM1与等级呈正相关。通过ELISA和ICC对标志物的循环水平的定量呈现相似的结果。观察到生物标志物与OS负相关(p<0.0001)。Cox回归分析得出的所有生物标志物都是良好的预后指标,并且与混杂因素无关。在应用组合统计时,生物标志物组实现了比单一标志物更高的灵敏度来定义生存.所有七种生物标志物的内部关联是显著的,提示TME成分之间的串扰和缺氧驱动的全身性炎症上调其他成分的表达。这是对标记物组的首次实验研究,该标记物组可以区分组织病理学等级,并使用液体活检描绘不同的存活率。这表明缺氧标志物可以成为个性化治疗的基石。iNOS的生物标志物组,HSP70,IL-6,VEGF,ET1,MMP14和ICAM1有望在HGG中进行预测。
High-grade gliomas (HGG) comprising WHO grades 3 and 4 have a poor overall survival (OS) that has not improved in the past decade. Herein, markers representing four components of the tumor microenvironment (TME) were identified to define their linked expression in TME and predict the prognosis in HGG, namely, interleukin6 (IL6, inflammation), inducible nitric oxide synthase(iNOS), heat shock protein-70 (HSP70, hypoxia), vascular endothelial growth receptor (VEGF), and endothelin1 (ET1) (angiogenesis) and matrix metalloprotease-14 (MMP14) and intercellular adhesion molecule1 (ICAM1, extracellular matrix). To establish a non-invasive panel of biomarkers for precise prognostication in HGG. Eighty-six therapy-naive HGG patients with 45 controls were analyzed for the defined panel. Systemic expression of extracellular/secretory biomarkers was screened dot-immune assay (DIA), quantified by ELISA, and validated by immunocytochemistry (ICC). Expression of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 was found to be positively associated with grade. Quantification of circulating levels of the markers by ELISA and ICC presented a similar result. The biomarkers were observed to negatively correlate with OS (p < 0.0001). Cox-regression analysis yielded all biomarkers as good prognostic indicators and independent of confounders. On applying combination statistics, the biomarker panel achieved higher sensitivity than single markers to define survival. The intra-association of all seven biomarkers was significant, hinting of a cross-talk between the TME components and a hypoxia driven systemic inflammation upregulating the expression of other components. This is a first ever experimental study of a marker panel that can distinguish between histopathological grades and also delineate differential survival using liquid biopsy, suggesting that markers of hypoxia can be a cornerstone for personalized therapy. The panel of biomarkers of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 holds promise for prognostication in HGG.