Abstract
Despite advances in biology and treatment modalities, the prognosis of glioblastoma (GBM) remains poor. Serum reflects disease macroenvironment and thus provides a less invasive means to diagnose and monitor a diseased condition. By employing 4-plex iTRAQ methodology, we identified 40 proteins with differential abundance in GBM sera. The high abundance of serum S100A8/S100A9 was verified by multiple reaction monitoring (MRM). ELISA and MRM-based quantitation showed a significant positive correlation. Further, an integrated investigation using stromal, tumor purity and cell type scores demonstrated an enrichment of myeloid cell lineage in the GBM tumor microenvironment. Transcript levels of S100A8/S100A9 were found to be independent poor prognostic indicators in GBM. Medium levels of pre-operative and three-month post-operative follow-up serum S100A8 levels predicted poor prognosis in GBM patients who lived beyond median survival. In vitro experiments showed that recombinant S100A8/S100A9 proteins promoted integrin signalling dependent glioma cell migration and invasion up to a threshold level of concentrations. Thus, we have discovered GBM serum marker by iTRAQ and verified by MRM. We also demonstrate interplay between tumor micro and macroenvironment and identified S100A8 as a potential marker with diagnostic and prognostic value in GBM.
Highlights
Despite advances in biology and treatment modalities, the prognosis of glioblastoma (GBM) remains poor
The two candidates, S100A8 and S100A9 were prioritized for verification based on their maximal abundance in GBM serum in our discovery phase
Serum protein levels and tumor transcript levels of S100A8 and S100A9 were used for detailed analysis to probe the role of these two proteins in GBM diagnosis and prognosis
Summary
Despite advances in biology and treatment modalities, the prognosis of glioblastoma (GBM) remains poor. The high abundance of serum S100A8/S100A9 was verified by multiple reaction monitoring (MRM). We demonstrate interplay between tumor micro and macroenvironment and identified S100A8 as a potential marker with diagnostic and prognostic value in GBM. Serum proteins can be utilized as biomarkers to diagnose and monitor disease progression in a less invasive manner. Reciprocal interactions between tumor and its micro and macro-environment play a decisive role in disease prognosis and have the potential for therapeutic intervention[11]. To examine the role of GBM serum proteins to monitor and influence the disease progression, we performed an unbiased quantitative differential proteomics of GBM patient sera, using iTRAQ, which revealed several potential candidate biomarkers. We performed a thorough examination of association between GBM educated macro and microenvironment utilizing our iTRAQ data and transcripts of high abundant serum protein in tumor. We further performed an in-depth investigation of their source of origin as well as diagnostic and prognostic capabilities of RNA and serum levels of these two proteins
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