CD63-positive extracellular vesicles are potential diagnostic biomarkers of pancreatic ductal adenocarcinoma

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest gastrointestinal cancers with a 5-year survival rate of less than 10%. Biomarkers for early PDAC detection are useful in treating patients with PDAC. Extracellular vesicles (EVs) are lipid-bound vesicles that are potential biomarkers of various diseases such as PDAC. In this study, we quantitatively measured the serum levels of EVs (CD63(+)-EVs) or platelet-derived EVs (CD41(+)- and CD61(+)-EVs) and evaluated their potential use as biomarkers of PDAC. Methods We measured the serum levels of CD63(+)-, CD41(+)-, CD61(+)-EVs using sandwich enzyme-linked immunosorbent assay based on Tim4 with specificity for phosphatidylserine on EVs in age- and sex-matched healthy controls (HCs, n = 39) and patients with PDAC (n = 39). We also examined the effect of tumor burden on the serum EV levels after surgical resection (n = 28). CA19-9, a clinical PDAC biomarker, was also measured for comparison. Results Serum levels of CD63(+)-EVs, CD41(+)-EVs, and CD61(+)-EVs were significantly increased in patients with PDAC compared to HCs. Receiver operating characteristic analysis revealed that CD63(+)-EVs exhibited the highest diagnostic performance to discriminate patients with PDAC from HCs (area under the curve (AUC): 0.846), which was comparable to CA19-9 (AUC: 0.842). CA19-9 showed lower AUC values in early stages (I-II, AUC: 0.814) than in late stages (III-IV, AUC: 0.883) PDAC. Conversely, CD63(+)-EVs, CD41(+)-EVs, and CD61(+)-EVs showed comparable AUCs between early- and late-stage PDAC. The combined use of CA19-9 and CD63(+)-EVs showed a higher diagnostic performance for early-stage PDAC (AUC: 0.903) than CA19-9. The serum levels of CD63(+)-EVs, CD41(+)-EVs, CD61(+)-EVs, and CA19-9 decreased significantly after surgical resection, demonstrating that EVs are increased in sera of patients depending on the tumor burden. Conclusions The serum levels of CD63(+)-EVs and platelet-derived EVs (CD41(+)-EVs, CD61(+)-EVs) are increased in patients with PDAC than HCs. Since CD63(+)-EVs showed a high AUC to discriminate patients with PDAC from HCs; they might be useful as potential biomarkers for PDAC.

Automated summary

In this study, it was found that serum levels of CD63(+)-EVs and platelet-derived EVs (CD41(+)-EVs, CD61(+)-EVs) were significantly increased in patients with PDAC compared to healthy controls. CD63(+)-EVs showed high diagnostic performance in discriminating patients with PDAC from healthy controls and could be potential biomarkers for PDAC.