Abstract
Perihilar cholangiocarcinoma (PHCCA) has a poor prognosis, mainly due to diagnosis at an advanced stage. Cripto-1 functions as an oncogene and is highly expressed in several human cancers, however, its clinical application in PHCCA is poorly understood. Herein, we identified that Cripto-1 was released by PHCCA cells via exosomes in vitro and in vivo. Furthermore, an ELISA method was developed to detect exosomal Cripto-1 in the serum of 115 PHCCA patients, 47 cholangitis patients and 65 healthy controls, and it was found that exosomal Cripto-1 was increased in PHCCA patients and associated with metastasis. Compared with traditional serum tumor markers, CA19-9 and CEA, exosomal Cripto-1 demonstrated a larger area under ROC curve for PHCCA diagnosis. The cutoff value of exosomal Cripto-1 was 0.82, achieving a sensitivity of 79.1% and a specificity of 87.5%. As expected, exosomal Cripto-1 levels in immunohistochemically Cripto-1-high cases were significantly elevated compared to in Cripto-1-low cases. When measured 1-week postoperatively, Cripto-1 levels decreased on average from 1.25(0.96-3.26) to 0.85(0.62-1.82). Immunohistochemistry analysis showed Cripto-1 expression was negatively correlated with E-cadherin and was an independent prognostic biomarker for poor survival in PHCCA patients. In conclusion, exosomal Cripto-1 in sera can reflect its expression in the tissue of PHCAA patients and has the potential be a non-invasive biomarker for diagnosis and prognosis of PHCCA.
Highlights
Perihilar cholangiocarcinoma (PHCCA), known as a Klatskin tumor, is a subtype of CCA, arising at or near the confluence of the right and left hepatic duct
Cripto-1 Is Secreted With Exosomes From PHCCA Cells
Exosomes purified from PHCAA cells showed enrichment of exosomal markers, CD81 and TSG101, compared to total cell lysis, and had no Calnexin expression, an endoplasmic reticulum marker known to be absent in exosomes and present in cells lysis (Figure 1A)
Summary
Perihilar cholangiocarcinoma (PHCCA), known as a Klatskin tumor, is a subtype of CCA, arising at or near the confluence of the right and left hepatic duct It accounts for more than 50% of total CCA cases and is characterized by high surgical difficulty and poor prognosis [1,2,3]. It has been reported that cancer cell-secreted exosomes can be transferred to recipient cells and promote tumor progression by enhancing immunosuppression, angiogenesis and metastatic dissemination [19]. These extracellular vesicles contain specific components, such as lipids, proteins, and nucleic acids, mirroring their cellular origin [20]. This study sought to assess the significance of Cripto-1 in prognosis in a retrospective cohort of PHCCA patients
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