Alpha-Fetoprotein, Protein Induced by Vitamin K Absence or Antagonist II and Glypican-3 for the Detection and Prediction of Hepatocellular Carcinoma in Patients with Cirrhosis of Viral Etiology

Caviglia, Gian Paolo; Ciruolo, Michela; Abate, Maria Lorena; Carucci, P.; Rolle, Emanuela; Rosso, Chiara; Olivero, Antonella; Troshina, Giulia; Risso, Alessandra; Nicolosi, Aurora; Ribaldone, Davide Giuseppe; Armandi, Angelo; Tandoi, Francesco; Saracco, Giorgio Maria; Bugianesi, Elisabetta; Ciancio, Alessia; Gaia, Silvia

doi:10.3390/cancers12113218

Cited by 35 publications

(27 citation statements)

References 34 publications

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“…Many recent studies evaluated individual and combined diagnostic values of serum alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP), glypican-3 (GPC3) and golgi protein 73 (GP73) in diagnosing HCC. [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75] One study by Li et al showed combination of serum levels of miR-122, GPC3 and AFP improved power of HCC detection. 66 Several studies showed that the sensitivity of circulating GPC3 is superior to AFP for detecting HCC.…”

Section: Discussionmentioning

confidence: 99%

Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis

Aydın¹,

Köksal²,

Thevenot³

et al. 2021

JHC

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Background and Aims: Hepatocellular carcinoma (HCC) developing in the context of preexisting cirrhosis is characterized by impaired autophagy that results in increased exosome release. This study was conducted to determine whether circulating exosomes expressing glypican 3 (GPC3) could be utilized as a biomarker for HCC detection and treatment response in patients with cirrhosis. Methods: Immunohistochemistry was performed to assess p62 and GPC3 expression in the lesion and adjacent tissue from cirrhosis with HCC. GPC3-enriched exosomes were captured by an enzyme-linked immunosorbent assay (ELISA). The diagnostic specificity of serum exosome-derived GPC3 (eGPC3) was determined using samples obtained from malignancyfree controls, malignancy-free cirrhotics, cirrhotics with confirmed HCC, and patients with a non-HCC malignancy. The performance of eGPC3 was validated using serum samples of HCC patients received chemotherapy. Results: We found that the expression of p62 and GPC3 was significantly increased in HCC tissues compared to adjacent cirrhotic liver. Impaired autophagy and exosome shedding were confirmed in HCC cell lines. Mass spectroscopic analysis revealed that GPC3 was enriched in exosomes isolated from HCC cell lines. An affinity ELISA assay was developed that specifically captures GPC3 positive exosomes in the serum. Total exosome concentration and eGPC3 were significantly elevated in cirrhotic patients with HCC as compared to the reference control groups. Furthermore, decreases in post-treatment exosome concentration and eGPC3 levels were more closely correlated with response to locoregional chemotherapy compared to change in serum AFP in HCC patients awaiting liver transplantation. Conclusion:We developed an affinity exosome capture assay to detect GPC3 enriched exosomes. Our preliminary assessment shows that GPC3 positive exosomes can be used for HCC detection and prediction of treatment outcomes.

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Section: Discussionmentioning

confidence: 99%

Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis

Aydın¹,

Köksal²,

Thevenot³

et al. 2021

JHC

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“…In agreement with previous studies performed in patients with NAFLD [ 39 , 40 ], we observed a good diagnostic accuracy for PIVKA-II (AUC = 0.853) and a moderate performance for AFP (AUC = 0.763). Interestingly, GPC-3 showed a higher accuracy compared to the results of our previous study carried out on a cohort of patients with viral related-HCC [ 18 ]. Possibly, both the diverse etiology and clinical characteristics of the patients included may have accounted for the discrepancy observed.…”

Section: Discussionmentioning

confidence: 73%

“…Among the traditional HCC biomarkers, protein induced by vitamin K absence or antagonist II (PIVKA-II), alone or in combination with alpha-fetoprotein (AFP), showed promising results for the early detection, and even for the prediction, of HCC in patients with cirrhosis of viral etiology [ 17 , 18 , 19 , 20 ]. However, the data on NAFLD-related HCC are scant.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of Oncogenesis, Adipose Tissue Dysfunction and Systemic Inflammation for the Detection of Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease

Caviglia

Armandi

Rosso

et al. 2021

Cancers

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Current surveillance strategy for patients with nonalcoholic fatty liver disease (NAFLD) at risk of hepatocellular carcinoma (HCC) development is unsatisfactory. We aimed to investigate the diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), glypican-3 (GPC-3), adiponectin, leptin and interleukin-6 (IL-6), alone or in combination, for the discrimination between NAFLD patients with or without HCC. The biomarkers were investigated in a cohort of 191 NAFLD patients (median age 62, 54–68 years; 121 males and 70 females) with advanced fibrosis/cirrhosis, 72 of whom had a diagnosis of HCC. PIVKA-II showed the best performance for the detection of HCC with an area under the curve (AUC) of 0.853, followed by adiponectin (AUC = 0.770), AFP (AUC = 0.763), GPC-3 (AUC = 0.759) and by IL-6 (AUC = 0.731), while the leptin values were not different between patients with and without HCC. The accuracy of the biomarkers’ combination was assessed by a stratified cross-validation approach. The combination of age, gender, PIVKA-II, GPC-3 and adiponectin further improved the diagnostic accuracy (AUC = 0.948); the model correctly identified the 87% of the patients. In conclusion, we developed a model with excellent accuracy for the detection of HCC that may be useful to improve the surveillance of NAFLD patients at risk of tumor development.

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“…In fact, hypoxia altering the actin molecules making up their cytoskeleton impairs the endocytosis of vitamin K, and the subsequent vitamin K deficiency leads to the release into the circulation of vitamin K deficient prothrombin without complete carboxylation [ 23 ]. On the other hand, PIVKA-II appears to be also involved in neo-angiogenesis [ 24 ] and able to act as a mitogen stimulating the growth of HCC cells [ 25 ], thus contributing to the increased risk of HCC in cirrhotic patients [ 26 , 27 ]. Altogether, these data support the interpretation that PIVKA-II production by cancer cells is increased by ischemia and tend to stimulate angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Modeling Hepatocellular Carcinoma Cells Dynamics by Serological and Imaging Biomarkers to Explain the Different Responses to Sorafenib and Regorafenib

Colombatto¹,

Demirtaş

Ricco³

et al. 2021

Cancers

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In advanced HCC, tyrosine-kinase inhibitors obtain partial responses (PR) in some patients and complete responses (CR) in a few. Better understanding of the mechanism of response could be achieved by the radiomic approach combining digital imaging and serological biomarkers (α-fetoprotein, AFP and protein induced by vitamin K absence-II, PIVKA-II) kinetics. A physic-mathematical model was developed to investigate cancer cells and vasculature dynamics in three prototype patients receiving sorafenib and/or regorafenib and applied in seven others for validation. Overall four patients showed CR, two PR, two stable-disease (SD) and two progressive-disease (PD). The rate constant of cancer cells production was higher in PD than in PR-SD and CR (median: 0.398 vs. 0.325 vs. 0.316 C × day−1). Therapy induced reduction of neo-angiogenesis was greater in CR than in PR-SD and PD (median: 83.2% vs. 29.4% and 2.0%), as the reduction of cell-proliferation (55.2% vs. 7.6% and 0.7%). An additional dose-dependent acceleration of tumor vasculature decay was also observed in CR. AFP and cancer cells followed the same kinetics, whereas PIVKA-II time/dose dependent fluctuations were influenced also by tissue ischemia. In conclusion, pending confirmation in a larger HCC cohort, modeling serological and imaging biomarkers could be a new tool for systemic therapy personalization.

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Alpha-Fetoprotein, Protein Induced by Vitamin K Absence or Antagonist II and Glypican-3 for the Detection and Prediction of Hepatocellular Carcinoma in Patients with Cirrhosis of Viral Etiology

Cited by 35 publications

References 34 publications

Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis

Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis

Biomarkers of Oncogenesis, Adipose Tissue Dysfunction and Systemic Inflammation for the Detection of Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease

Modeling Hepatocellular Carcinoma Cells Dynamics by Serological and Imaging Biomarkers to Explain the Different Responses to Sorafenib and Regorafenib

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