CD63-positive extracellular vesicles are potential diagnostic biomarkers of pancreatic ductal adenocarcinoma
Haruki Odaka, Keiko Hiemori, Asako Shimoda, Kazunari Akiyoshi, Hiroaki Tateno
Abstract
Abstract 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.