Characterizing the Linkage of Systemic Hypoxia and Angiogenesis in High-Grade Glioma to Define the Changes in Tumor Microenvironment for Predicting Prognosis

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Neuroscience Pub Date : 2024-07-05 DOI:10.1007/s12031-024-02240-4

Richa Shrivastava, Puneet Gandhi, Sandeep K. Sorte, Adesh Shrivastava

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Abstract

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.

Graphical Abstract

The cross-talk between the systemic biomarkers of four different partakers of tumor microenvironment

Abstract Image

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表征高级别胶质瘤中全身缺氧与血管生成的联系，确定肿瘤微环境的变化以预测预后。

高级别胶质瘤（HGG）包括WHO 3级和4级，其总生存率（OS）很低，在过去十年中一直没有改善。在此，研究人员确定了代表肿瘤微环境（TME）四种成分的标记物，以确定它们在TME中的关联表达，并预测HGG的预后，这四种标记物分别是白细胞介素6（IL6，炎症）、诱导型一氧化氮合酶（iNOS）、热休克蛋白-70（HSP70，缺氧）和热休克蛋白-70、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）以及基质金属蛋白酶-14（MMP14）和细胞间粘附分子1（ICAM1，细胞外基质）。建立一个非侵入性生物标记物面板，用于准确预测 HGG 的预后。研究人员对86名未经治疗的HGG患者和45名对照组患者进行了分析。通过点免疫测定（DIA）筛查细胞外/分泌生物标志物的全身表达，通过酶联免疫吸附试验（ELISA）量化，并通过免疫细胞化学（ICC）验证。结果发现，iNOS、HSP70、IL-6、VEGF、ET1、MMP14 和 ICAM1 的表达与分级呈正相关。通过 ELISA 和 ICC 对这些标记物的循环水平进行定量也得出了类似的结果。观察发现，生物标志物与 OS 呈负相关（p

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来源期刊

Journal of Molecular Neuroscience 医学-神经科学

CiteScore

6.60

自引率

3.20%

发文量

142

审稿时长

1 months

期刊介绍： The Journal of Molecular Neuroscience is committed to the rapid publication of original findings that increase our understanding of the molecular structure, function, and development of the nervous system. The criteria for acceptance of manuscripts will be scientific excellence, originality, and relevance to the field of molecular neuroscience. Manuscripts with clinical relevance are especially encouraged since the journal seeks to provide a means for accelerating the progression of basic research findings toward clinical utilization. All experiments described in the Journal of Molecular Neuroscience that involve the use of animal or human subjects must have been approved by the appropriate institutional review committee and conform to accepted ethical standards.