Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
Cancer Res Commun. 2023 Sep 15;3(9):1862-1874. doi: 10.1158/2767-9764.CRC-23-0087.
Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP.
EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.
促红细胞生成素产生肝细胞 Ephrin 受体 A2（EphA2）的裂解触发恶性进展，并产生可在胰腺导管腺癌患者血清中检测到的 N 端片段（EphA2-NF）。我们建立了一种用于 EphA2-NF 的定量自动化化学发光免疫分析，并在测试和验证队列中评估了血清 EphA2-NF 水平作为诊断胰腺导管腺癌的生物标志物。EphA2-NF 值升高（高于截止值：平均值±SD）在超过一半的 I/II 期胰腺导管腺癌患者中。在接受胰腺导管腺癌标准化疗[吉西他滨加 nab-紫杉醇（GnP）]的患者中，EphA2-NF 血清水平升高的患者中位生存时间是低于截止值的患者的一半。具有癌前胰腺导管腺癌病变的导管内乳头状黏液性肿瘤（IPMN）患者也表现出高血清 EphA2 水平，这与胰管增大和某些情况下胰腺导管腺癌的发展有关。免疫组化显示，具有胰腺导管腺癌的 IPMN 中 EphA2-NF 染色丢失，但在正常上皮或无胰腺导管腺癌的 IPMN 中则没有，无论组织学分级如何。这些结果表明，EphA2 裂解是胰腺导管腺癌发展过程中很早就发生的重要事件，并且 EphA2-NF 的释放可以在血清中检测到。因此，血清 EphA2-NF 可以作为非常早期胰腺导管腺癌和高危 IPMN 发展为胰腺导管腺癌的诊断生物标志物，以及 GnP 化疗后的预后生物标志物。
EphA2 N 端缺失参与高危 IPMN 发展为胰腺导管腺癌，裂解产生的 EphA2-NF 可用作血清生物标志物，用于诊断胰腺导管腺癌并预测高危 IPMN 发展为胰腺导管腺癌。
