Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

Arbelaiz, Ander; Azkargorta, Mikel; Krawczyk, Marcin; Santos‐Laso, Álvaro; Lapitz, Ainhoa; Perugorria, María J.; Erice, Oihane; González, Esperanza; Jiménez-Agüero, Raúl; Lacasta, Adelaida; Ibarra, Cesar; Sánchez-Campos, Alberto; Jimeno, J.P.; Lammert, Frank; Milkiewicz, Piotr; Marzioni, Marco; Macı́as, Rocı́o I.R.; Marin, José J.G.; Patel, Tushar; Gores, Gregory J.; Martínez, I. Mascarell; Elortza, Félix; Falcón‐Pérez, Juan Manuel; Bujanda, Luís; Bañales, Jesús M.

doi:10.1002/hep.29291

Cited by 226 publications

(193 citation statements)

References 43 publications

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“…A panel of miRNAs isolated from EVs in bile had a reported sensitivity of 67% and a specificity of 96% for the diagnosis of cholangiocarcinoma 60 . Furthermore, a separate proteomic analysis indicated that greater levels of oncogenic proteins are present in EVs obtained from cultures of human cholangiocarcinoma cells versus those derived from nonmalignant human cholangiocytes 61 . In addition, Severino et al 62 demonstrated that patients with malignant biliary strictures have a significantly higher concentration of EVs in bile than those with nonmalignant strictures (2.4 × 10 15 versus 1.6 × 10 14 nanoparticles/l in the discovery cohort, P <0.0001; 4.0 × 10 15 versus 1.3 × 10 14 nanoparticles/l in the verification cohort, P <0.0001).…”

Section: Standard Of Care: Diagnosis and Therapymentioning

confidence: 99%

Cholangiocarcinoma — evolving concepts and therapeutic strategies

et al. 2017

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Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

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Section: Standard Of Care: Diagnosis and Therapymentioning

confidence: 99%

Cholangiocarcinoma — evolving concepts and therapeutic strategies

et al. 2017

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“…Proteins within serum EVs were also found to be excellent biomarkers, able to differentiate between patients with primary sclerosing cholangitis (PSC) and those with CCA or HCC, as well as normal liver controls . Because PSC is the most important risk factor for perihilar CCA in the United States and because, clinically, it is often difficult to differentiate between a nonmalignant stricture in PSC and frank CCA, the differentiation between PSC and CCA was of utmost importance.…”

Section: Extracellular Vesiclesmentioning

confidence: 99%

Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

et al. 2019

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Intrahepatic cholangiocarcinoma (iCCA) has over the last 10‐20 years become the focus of increasing concern, largely due to its rising incidence and high mortality rates worldwide. The significant increase in mortality rates from this primary hepatobiliary cancer, particularly over the past decade, has coincided with a rapidly growing interest among clinicians, investigators, and patient advocates to seek greater mechanistic insights and more effective biomarker‐driven targeted approaches for managing and/or preventing this challenging liver cancer. In addition to discussing challenges posed by this aggressive cancer, this review will emphasize recent epidemiological, basic, and translational research findings for iCCA. In particular, we will highlight emerging demographic changes and evolving risk factors, the critical role of the tumor microenvironment, extracellular vesicle biomarkers and therapeutics, intertumoral and intratumoral heterogeneity, and current and emerging targeted therapies regarding iCCA. Specifically, recent evidence linking non–bile duct medical conditions, such as nonalcoholic fatty liver disease and nonspecific cirrhosis, to intrahepatic cholangiocarcinogenesis together with geographic and ethnic variation will be assessed. Recent developments concerning the roles played by transforming growth factor‐β and platelet‐derived growth factor D in driving the recruitment and expansion of cancer‐associated myofibroblasts within cholangiocarcinoma (CCA) stroma as well as their therapeutic implications will also be discussed. In addition, the potential significance of extracellular vesicles as bile and serum biomarkers and therapeutic delivery systems for iCCA will be described. An integrated systems approach to classifying heterogeneous iCCA subtypes will be further highlighted, and recent clinical trials and emerging targeted therapies will be reviewed, along with recommendations for future translational research opportunities. Established international CCA networks are now facilitating collaborations aimed at advancing iCCA translational and clinical research.

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“…90 Recently, a study screening for noninvasive biomarkers for diagnosis of primary sclerosing cholangitis (PSC), CCA, and HCC, identified several proteins that are specifically enriched in serum-derived EVs, including aminopeptidase N (AMPN), gamma-glutamyltransferase 1(GGT1), polymeric immunoglobulin receptor (PIGR), vanin 1 (VNN1), immunoglobulin heavy constant alpha 1 (IGHA1), C-reactive protein (CRP), alpha-1-acid glycoprotein 1 (A1AG1), and alectin-3-binding protein (LG3BP). 91 …”

Section: Evs As Potential Biomarkers For Liver Diseasesmentioning

confidence: 99%

Decoding the role of extracellular vesicles in liver diseases

2017

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Cell-to-cell communication is a fascinating process that is essential for maintaining tissue and whole-body homeostasis. Extracellular vesicles (EVs) are cell-derived membrane-bound nanoparticles that are a means of communication between cells. Accumulating evidence indicates that EVs can render either beneficial or harmful outcomes, depending on the specific cargos (e.g. proteins, lipids, RNAs) transferred between cells. EVs also have great value as diagnostic and prognostic markers of disease because they are present in a variety of biological fluids and carry bioactive molecules from their cells or tissues of origin. Liver cells can both release and receive EVs derived from other cells and emerging evidence indicates that liver EVs play important roles in the pathogenesis of various liver diseases, including liver cancer, viral hepatitis, non-alcoholic fatty liver disease, and alcoholic liver disease. This review provides an overview of the biogenesis and secretion of EVs and summarizes the most recent advances in understanding the role of EVs in liver physiology and diseases. Additionally, we discuss potential applications of liver EVs as biomarkers and in therapeutic approaches to treat liver diseases.

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Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

Abstract: Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (Hepatology 2017;66:1125-1143).

Cited by 226 publications

References 43 publications

Cholangiocarcinoma — evolving concepts and therapeutic strategies

Cholangiocarcinoma — evolving concepts and therapeutic strategies

Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

Decoding the role of extracellular vesicles in liver diseases

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