Circulating cancer‐associated extracellular vesicles as early detection and recurrence biomarkers for pancreatic cancer

• Published in: Cancer science Vol. 113; no. 10; pp. 3498 - 3509
• Main Authors: Yoshioka, Yusuke, Shimomura, Manami, Saito, Keigo, Ishii, Hideshi, Doki, Yuichiro, Eguchi, Hidetoshi, Nakatsura, Tetsuya, Itoi, Takao, Kuroda, Masahiko, Mori, Masaki, Ochiya, Takahiro
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2022; John Wiley and Sons Inc
• Subjects: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Biological markers; Biomarkers; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal - pathology; Computed tomography; Disease; Diseases; early diagnosis; Epidermal growth factor; ErbB Receptors; Extracellular vesicles; Extracellular Vesicles - pathology; Humans; Immunoblotting; liquid biopsy; Medical prognosis; Methods; Original; ORIGINAL ARTICLES; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Pancreatitis; Patients; Proteins; proteomic analysis; Proteomics; Relapse; Review boards; Surgery; Tumors; Ultracentrifugation; Japan; early diagnosis; extracellular vesicles; liquid biopsy; pancreatic ductal adenocarcinoma; proteomic analysis
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.15500

Early detection of pancreatic ductal adenocarcinoma (PDAC) is essential for improving patient survival rates, and noninvasive biomarkers are urgently required to identify patients who are eligible for curative surgery. Here, we examined extracellular vesicles (EVs) from the serum of PDAC patients to determine their ability to detect early‐stage disease. EV‐associated proteins purified by ultracentrifugation and affinity columns underwent proteomic analysis to identify novel PDAC markers G protein‐coupled receptor class C group 5 member C (GPRC5C) and epidermal growth factor receptor pathway substrate 8 (EPS8). To verify the potency of GPRC5C‐ or EPS8‐positive EVs as PDAC biomarkers, we analyzed EVs from PDAC patient blood samples using ultracentrifugation in two different cohorts (a total of 54 PDAC patients, 32 healthy donors, and 22 pancreatitis patients) by immunoblotting. The combination of EV‐associated GPRC5C and EPS8 had high accuracy, with area under the curve values of 0.922 and 0.946 for distinguishing early‐stage PDAC patients from healthy controls in the two cohorts, respectively, and could detect PDAC patients who were negative for CA19‐9. Moreover, we analyzed 30 samples taken at three time points from 10 PDAC patients who underwent surgery: before surgery, after surgery, and recurrence as an early‐stage model. These proteins were detected in EVs derived from preoperative and recurrence samples. These results indicated that GPRC5C‐ or EPS8‐positive EVs were biomarkers that have the potential to detect stage I early pancreatic cancer and small recurrent tumors detected by computed tomography. Early detection of pancreatic ductal adenocarcinoma (PDAC) is essential for improving patient survival rates. This study demonstrated that PDAC patients who were negative for CA19‐9 could be detected by extracellular vesicles (EV)‐associated GPRC5C or EPS8, and these EV‐associated proteins showed high accuracy for distinguishing patients with stage I early pancreatic cancer from healthy controls. EV‐associated GPRC5C and EPS8 will contribute to the early detection and help in the design of potential curative surgical options.