[Show abstract][Hide abstract] ABSTRACT: Background:
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third most lethal cancer worldwide. The epithelial to mesenchymal transition (EMT) describes the transformation of well-differentiated epithelial cells to a de-differentiated phenotype and plays a central role in the invasion and intrahepatic metastasis of HCC cells. Modulation of the transforming growth factor-β (TGF-β) signaling is known to induce various tumor-promoting and EMT-inducing pathways in HCC. The meta-analysis of a panel of EMT gene expression studies revealed that neuropilin 2 (NRP2) is significantly upregulated in cells that have undergone EMT induced by TGF-β. In this study we assessed the functional role of NRP2 in epithelial and mesenchymal-like HCC cells and focused on the molecular interplay between NRP2 and TGF-β/Smad signaling.
NRP2 expression was analyzed in human HCC cell lines and tissue arrays comprising 133 HCC samples. Cell migration was examined by wound healing and Transwell assays in the presence and absence of siRNA against NRP2. NRP2 and TGF-β signaling were analyzed by Western blotting and confocal immunofluorescence microscopy.
We show that NRP2 is particularly expressed in HCC cell lines with a dedifferentiated, mesenchymal-like phenotype. NRP2 expression is upregulated by the canonical TGF-β/Smad signaling while NRP2 expression has no impact on TGF-β signaling in HCC cells. Reduced expression of NRP2 by knock-down or inhibition of TGF-β signaling resulted in diminished cell migration independently of each other, suggesting that NRP2 fails to collaborate with TGF-β signaling in cell movement. In accordance with these data, elevated levels of NRP2 correlated with a higher tumor grade and less differentiation in a large collection of human HCC specimens.
These data suggest that NRP2 associates with a less differentiated, mesenchymal-like HCC phenotype and that NRP2 plays an important role in tumor cell migration upon TGF-β-dependent HCC progression.
[Show abstract][Hide abstract] ABSTRACT: Acute kidney injury (AKI) is a common complication in patients with liver cirrhosis and its impact on the clinical course is increasingly recognized. Diagnostic classification systems for AKI in cirrhosis have been suggested. The prognostic significance of the respective AKI stages remains to be evaluated in decompensated cirrhosis with ascites.
Data of consecutive patients with cirrhosis and ascites undergoing paracentesis at a tertiary care center were analyzed. AKI was defined as an increase in serum creatinine of ≥0.3mg/dL or by ≥50% within 7 days after paracentesis, and classified according to (i) revised AKIN criteria and (ii) modified AKI criteria for cirrhosis (C-AKI). In contrast to AKIN, C-AKI stage A discriminates prognosis based on an absolute creatinine cut-off at <1.5mg/dL vs. C-AKI stage B at ≥1.5mg/dL..
The final study cohort included 239 patients. Median transplant-free survival was 768 days (95%CI: 331-1205 days) without AKI, 198(0-446) in AKI-1, 91(0-225) in AKI-2, 19(0-40) and in AKI-3, whereas it was 89(20-158) days in C-AKI-A, 384(0-1063) in C-AKI-B, and 22(7-776) in C-AKI-C. Mild AKI was already associated with significantly increased 30-day mortality (AKI-1:26.4%, C-AKI-A:33.3%) as compared to patients without AKI (14.3%), even when serum creatinine remained within normal range (<1.2mg/dL) we observed a significant 30-day mortality.
AKIN criteria - considering small increases in serum creatinine rather than absolute thresholds - seem to be more accurate for estimating prognosis of AKI after paracentesis than C-AKI criteria. Even patients developing AKI-1 with "normal" serum creatinine are at increased risk for mortality.
This article is protected by copyright. All rights reserved.
No preview · Article · May 2015 · Journal of Gastroenterology and Hepatology
[Show abstract][Hide abstract] ABSTRACT: Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate stage HCC (BCLC-B). Further improvement of the use of TACE was subject of intense clinical research over the past years. The introduction of DEB-TACE brought more technical standardization and reduction of TACE related toxicity. The use of dynamic radiologic response evaluation criteria (EASL, mRECIST), uncovered the prognostic significance of objective tumor response. Finally, new approaches for better patient selection for initial and subsequent TACE treatment schedules will limit the use of TACE to some extent but have the potential to improve outcome for patients at risk for TACE-induced harm.
Preview · Article · Feb 2015 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Despite the important clinical value of hepatic venous pressure gradient (HVPG) and its increasing use, no specific balloon occlusion catheters have been designed to cannulate liver veins. The aim of the study was to evaluate the clinical applicability of a novel balloon(NC) occlusion catheter specifically designed for for HVPG measurement.
Comparison of a new CE-certified 7 french balloon occlusion catheter with a 150° angled tip and radiopaque markers, (NC, Pejcl Medizintechnik, Austria) to a commonly used straight balloon catheter (SC, Boston Scientific, USA). Successful liver vein cannulaton rate, need for extra equipment, and total fluoroscopy time were recorded. Experts (>200) and novices (<20) in HVPG measurements were evaluated separately.
566 HVPG measurements performed by 11 investigators (5 experts and 6 novices) were analzyed. Overall, HVPG could be successfully measured in 98.7% of cases. The rate of successful liver vein cannulation at first attempt was significantly higher among experts when compared to novices (87.3%vs.67.3%,p<0.001). Moreover, the rate of successful liver vein cannulation without need for any additional equipment was higher when using the NC, both among experts (NC:91.9%vs.SC:80.6%,p=0.03) and novices (NC:73.3%vs.SC:50.7%,p=0.001). The mean fluoroscopy time needed to cannulate the hepatic vein was significantly shorter in experts as compared to novices (2.37(0.10-26)vs.5.2(0.6-30.2)minutes,p<0.0001), but not significantly different between catheters.
Both novices and experts achieve higher liver vein cannulation rates using the new specifically designed catheter. The use of the novel catheter might increase rates of successful liver vein cannulation and reduce the need for additional equipment, especially in novices. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Jan 2015 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Background and Aim
The aim of this study was to assess the impact of proton pump inhibitor (PPI) intake on the development of spontaneous bacterial peritonitis (SBP) or other infections, as well as on mortality, in a thoroughly documented cohort of patients with cirrhosis and ascites.
Patients and Methods
We performed a retrospective analysis of follow-up data from 607 consecutive patients with cirrhosis undergoing their first paracentesis at a tertiary center. A binary logistic regression model investigating the association between PPI intake and SBP at the first paracentesis was calculated. Competing risk analyses and Cox models were used to investigate the effect of PPIs on the cumulative incidence of SBP or other infections and transplant-free survival, respectively. Adjustments were made for age, hepatocellular carcinoma, history of variceal bleeding, varices and model of end-stage liver disease score.
Eighty-six percent of patients were receiving PPIs. After adjusting for potential confounding factors, PPI intake was neither associated with increased SBP prevalence at the first paracentesis (odds ratio (OR):1.11,95% confidence interval (95%CI):0.6–2.06; P = 0.731) nor cumulative incidence of SBP (subdistribution hazard ratio (SHR): 1.38; 95%CI:0.63–3.01; P = 0.42) and SBP or other infections (SHR:1.71; 95%CI:0.85–3.44; P = 0.13) during follow-up. Moreover, PPI intake had no impact on transplant-free survival in both the overall cohort (hazard ratio (HR):0.973,95%CI:0.719–1.317; P = 0.859) as well as in the subgroups of patients without SBP (HR:1.01,95%CI:0.72–1.42; P = 0.971) and without SBP or other infections at the first paracentesis (HR:0.944,95%CI:0.668–1.334; P = 0.742).
The proportion of cirrhotic patients with PPI intake was higher than in previous reports, suggesting that PPI indications were interpreted liberally. In our cohort with a particularly high prevalence of PPI intake, we observed no association between PPIs and SBP or other infections, as well as mortality. Thus, the severity of liver disease and other factors, rather than PPI treatment per se may predispose for infectious complications.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
In hepatocellular carcinoma (HCC), intrahepatic metastasis frequently correlates with epithelial to mesenchymal transition (EMT) of malignant hepatocytes. Several mechanisms have been identified to be essentially involved in hepatocellular EMT, among them transforming growth factor (TGF)-β signaling. Here we show the up-regulation and activation of the receptor tyrosine kinase Axl in EMT-transformed hepatoma cells. Knockdown of Axl expression resulted in abrogation of invasive and transendothelial migratory abilities of mesenchymal HCC cells in vitro and Axl overexpression-induced metastatic colonization of epithelial hepatoma cells in vivo. Importantly, Axl knockdown severely impaired resistance to TGF-β-mediated growth inhibition. Analysis of the Axl interactome revealed binding of Axl to 14-3-3ζ, which is essentially required for Axl-mediated cell invasion, transendothelial migration, and resistance against TGF-β. Axl/14-3-3ζ signaling caused phosphorylation of Smad3 linker region (Smad3L) at Ser213, resulting in the up-regulation of tumor-progressive TGF-β target genes such as PAI1, MMP9, and Snail as well as augmented TGF-β1 secretion in mesenchymal HCC cells. Accordingly, high Axl expression in HCC patient samples correlated with elevated vessel invasion of HCC cells, higher risk of tumor recurrence after liver transplantation, strong phosphorylation of Smad3L, and lower survival. In addition, elevated expression of both Axl and 14-3-3ζ showed strongly reduced survival of HCC patients.
Our data suggest that Axl/14-3-3ζ signaling is central for TGF-β-mediated HCC progression and a promising target for HCC therapy.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is a frequent cancer with limited treatment options and poor prognosis. Tumorigenesis has been linked with macrophage-mediated chronic inflammation and diverse signalling pathways, including the epidermal growth factor receptor (EGFR) pathway. The precise role of EGFR in HCC is unknown, and EGFR inhibitors have shown disappointing clinical results. Here we discover that EGFR is expressed in liver macrophages in both human HCC and in a mouse HCC model. Mice lacking EGFR in macrophages show impaired hepatocarcinogenesis, whereas mice lacking EGFR in hepatocytes unexpectedly develop more HCC owing to increased hepatocyte damage and compensatory proliferation. Mechanistically, following interleukin-1 stimulation, EGFR is required in liver macrophages to transcriptionally induce interleukin-6, which triggers hepatocyte proliferation and HCC. Importantly, the presence of EGFR-positive liver macrophages in HCC patients is associated with poor survival. This study demonstrates a tumour-promoting mechanism for EGFR in non-tumour cells, which could lead to more effective precision medicine strategies.
Full-text · Article · Aug 2014 · Nature Cell Biology