Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

Irvine, Katharine M.; Wockner, Leesa; Hoffmann, Isabell; Horsfall, Leigh; Fagan, Kevin J.; Bijin, Veonice Au; Lee, Bernett; Clouston, Andrew D.; Lampe, Guy; Connolly, John E.; Powell, Elizabeth E.

doi:10.1371/journal.pone.0167001

Cited by 32 publications

(48 citation statements)

References 31 publications

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“…our study for the first time demonstrates its utility as a circulating PDAC biomarker in patients (Bennewith et al, 2009;Neesse et al, 2011). Both MMP7 and CCN2 have been associated with poor prognosis in different types of cancer (Klupp et al, 2016;Sun et al, 2017) and with fibrotic or inflammatory diseases (Dendooven et al, 2011;Irvine et al, 2016). However, our results suggest that an improvement in the specificity of MMP7 and CCN2 results from the inclusion of additional biomarkers.…”

Section: Discussionmentioning

confidence: 62%

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Soluble stroma‐related biomarkers of pancreatic cancer

et al. 2018

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The clinical management of pancreatic ductal adenocarcinoma (PDAC) is hampered by the lack of reliable biomarkers. This study investigated the value of soluble stroma‐related molecules as PDAC biomarkers. In the first exploratory phase, 12 out of 38 molecules were associated with PDAC in a cohort of 25 PDAC patients and 16 healthy subjects. A second confirmatory phase on an independent cohort of 131 PDAC patients, 30 chronic pancreatitis patients, and 131 healthy subjects confirmed the PDAC association for MMP7, CCN2, IGFBP2, TSP2, sICAM1, TIMP1, and PLG. Multivariable logistic regression model identified biomarker panels discriminating respectively PDAC versus healthy subjects (MMP7 + CA19.9, AUC = 0.99, 99% CI = 0.98–1.00) (CCN2 + CA19.9, AUC = 0.96, 99% CI = 0.92–0.99) and PDAC versus chronic pancreatitis (CCN2 + PLG+FN+Col4 + CA19.9, AUC = 0.94, 99% CI = 0.88–0.99). Five molecules were associated with PanIN development in two GEM models of PDAC (PdxCre/LSL‐KrasG12D and PdxCre/LSL‐KrasG12D/+/LSL‐Trp53R172H/+), suggesting their potential for detecting early disease. These markers were also elevated in patient‐derived orthotopic PDAC xenografts and associated with response to chemotherapy. The identified stroma‐related soluble biomarkers represent potential tools for PDAC diagnosis and for monitoring treatment response of PDAC patients.

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Section: Discussionmentioning

confidence: 62%

“…Both MMP7 and CCN2 have been associated with poor prognosis in different types of cancer (Klupp et al , ; Sun et al , ) and with fibrotic or inflammatory diseases (Dendooven et al , ; Irvine et al , ). However, our results suggest that an improvement in the specificity of MMP7 and CCN2 results from the inclusion of additional biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Soluble stroma‐related biomarkers of pancreatic cancer

et al. 2018

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“…Previous studies have reported MMP-7 as a diagnostic or prognostic marker for various malignancies, including cholangiocarcinoma, pancreatic carcinoma, and gastric cancer, as well as fibrosis of lung and liver (35–39). Of specific relevance to our findings, MMP-7 was previously reported as elevated in serum and liver samples from subjects with BA after surgical treatment (40, 41), correlating with the severity of fibrosis regardless of the degree of jaundice clearance (41).…”

Section: Discussionmentioning

confidence: 99%

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

et al. 2017

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Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with gamma-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, is released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.

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“…The increased presence of MMP‐7 in human serum has been implicated in the pathogenesis of acute and chronic inflammatory conditions of the liver . Thus, we measured the serum levels of MMP‐7 in three group of mice.…”

Section: Resultsmentioning

confidence: 99%

“…The increased presence of MMP-7 in human serum has been implicated in the pathogenesis of acute and chronic inflammatory conditions of the liver. (28,29) Thus, we measured the serum levels of MMP-7 in three group of mice. At 2 weeks postinoculation higher levels of MMP-7 (P < 0.0005) were detected in serum of T R(VP2,VP4)inoculated mice than saline-inoculated controls (Fig.…”

Section: Increased Mmp-7 Serum Levels In T R(vp2vp4) -Inoculated Micementioning

confidence: 99%

Rotavirus Reassortant–Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia

et al. 2020

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Background and Aims Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end‐stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end‐stage liver disease requiring liver transplantation for survival. Approach and Results In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV‐infected pups succumb by day of life 14. Thus, in this study we generated an RRV‐TUCH rotavirus reassortant (designated as TR(VP2,VP4)) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3‐5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. Conclusions This model of rotavirus‐induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.

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Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers

Cited by 32 publications

References 31 publications

Soluble stroma‐related biomarkers of pancreatic cancer

Soluble stroma‐related biomarkers of pancreatic cancer

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

Rotavirus Reassortant–Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia

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