Characterizing the linkage of systemic hypoxia and angiogenesis in high grade glioma to define the changes in tumor microenvironment for predicting prognosis

Abstract Background High-grade gliomas (HGG) comprising WHO-grades 3and4 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 nitrous-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). Objective To establish a non invasive panel of biomarkers for precise prognostication in HGG Material and methods 86 therapy-naive HGG patients with 45 controls were analysed for the defined panel. Systemic-expression of extracellular/secretory biomarkers was screened dot-immune-assay(DIA), quantified by ELISA and validated by Immunocytochemistry(ICC). Results Expression of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, 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; 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 crosstalk between the TME components and a hypoxia driven systemic inflammation up-regulating the expression of other components. Conclusion 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.