Decreased serum thrombospondin-1 levels in pancreatic ductal adenocarcinoma patients: an early indicator of disease or diabetes mellitus development?

Abstract

Introduction: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Aims: Serum protein profiles in patients with pre-clinical disease and at diagnosis were investigated. Patients & methods: Serum from cases up to 4 years prior to diagnosis of PDAC and controls enrolled on the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, n=174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease and from healthy subjects (n=199). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n=150). Validation was undertaken using multiple reaction monitoring (MRM) and/or western blotting in all 373 human samples and in a KPC mouse model. Results: iTRAQ identified thrombospondin-1 (TSP-1) as down-regulated pre-clinically and in diagnosed patients. MRM confirmed significant down-regulation of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 (AUC= 0.86), significantly outperformed both markers alone (0.69 & 0.77 respectively). TSP-1 was also decreased in PDAC patients compared to healthy controls (P<0.05), patients with benign biliary obstruction (P<0.01) and in serum of KPC mice with PDAC. Low levels of TSP-1 correlated with poorer survival pre-clinically (P<0.05) and at diagnosis (P<0.02). Reduced TSP-1 levels were observed in PDAC patients with a confirmed diabetes mellitus (P<0.04). The decrease in TSP-1 compared to healthy controls was only observed in PDAC patients with diabetes (P<0.009). Conclusion: Circulating TSP-1 levels decrease during the development of PDAC. The influence of diabetes mellitus on biomarker behavior should be considered in future studies.