Tumor angiogenesis proteome dynamic changes across different grades of gliomas: Analysis within the framework of 3P medical approaches

Objective Glioma is highly neovascularized, which is a pathological hallmark. Tumor angiogenesis molecular pattern alterations remain unclear. This study aimed at the use of proteome-centered multiomics to identify tumor angiogenesis molecular pattern alteration and biomarker-sets with laser-capture microdissection (LCM)-isolated neovascular tissues from different stages of gliomas in the framework of predictive, preventive and personalized medicine (PPPM; 3PM). Methods Different stages (0, II, III, IV) of glioma neovascular tissues were isolated with LCM, followed by protein extraction and six-plex iTRAQ quantitative proteomics analysis. Proteomic data were integrated with transcriptomic data and clinical data from the Cancer Genome Atlas database (TCGA), and the Drug-Gene Interaction Database (DGIdb) to find key molecules and targeted drugs, followed by experiment validation. Results Totally 837 differentially abundant proteins (DAPs) were identified in different grades of glioma neovascular tissues relative to controls, which revealed significant dynamic change trends of 20 protein-molecular-networks, 88 signaling-pathways, and 172 hub-molecules. Integrative analysis of these DAPs and transcriptomic data found 35 target molecules, followed by validation in different stages (0, II, III, IV) of glioma clinical samples. The DGIdb drug analysis found that these target molecules EGFR, MMP9, ACTB, SERPINE1, BTK, and CAMK2B were matched to 58 FDA-approved anti-tumor drugs in clinical use; of them, the inhibitory effects of temozolomide and bevacizumab, targeting EGFR and MMP9 in glioma, were verified at cellular and animal levels. Conclusions This study provides the first large-scale proteomic landscape and biomarker-sets for glioma angiogenesis, and even for tumor angiogenesis. These findings hold potential for predictive diagnosis and targeted prevention of glioma progression, and also angiogenesis-targeting therapeutic efficacy provides a scientific basis for biomarker-guided, personalized drug therapy in glioma clinical management. Significance: Tumor angiogenesis is tightly associated with the malignancy of glioma, and is the crucial targets for anti-angiogenesis therapy. The detailed molecular profiling of tumor angiogenesis has not been clarified, which hinders its application in clinical care. Our study shows comprehensive proteome-centered multiomics molecular landscape and biomarker-sets for glioma angiogenesis, and reveals stratification and stage-specific molecular patterns of tumor angiogenesis relevant to improve 3P medical approaches in glioma.