Isabelle Colle

Angiogenesis in liver disease

Angiogenesis and disruption of liver vascular architecture have been linked to progression to cirrhosis and liver cancer (HCC) in chronic liver diseases, which contributes both to increased hepatic vascular resistance and portal hypertension and to decreased hepatocyte perfusion. On the other hand, recent evidence shows that angiogenesis modulates the formation of portal-systemic collaterals and the increased splanchnic blood flow which are involved in the life threatening complications of cirrhosis. Finally, angiogenesis plays a key role in the growth of tumours, suggesting that interference with angiogenesis may prevent or delay the development of HCC. This review summarizes current knowledge on the molecular mechanisms of liver angiogenesis and on the consequences of angiogenesis in chronic liver disease. On the other hand, it presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and its potential role in preventing transition to cirrhosis, development of portal hypertension and its consequences, and its application in the treatment of hepatocellular carcinoma.

Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

Experimental mouse models for hepatocellular carcinoma research

Every year almost 500,000 new patients are diagnosed with hepatocellular carcinoma (HCC), a primary malignancy of the liver that is associated with a poor prognosis. Numerous experimental models have been developed to define the pathogenesis of HCC and to test novel drug candidates. This review analyses several mouse models useful for HCC research and points out their advantages and weaknesses. Chemically induced HCC mice models mimic the injury‐fibrosis‐malignancy cycle by administration of a genotoxic compound alone or, if necessary, followed by a promoting agent. Xenograft models develop HCC by implanting hepatoma cell lines in mice, either ectopically or orthotopically; these models are suitable for drug screening, although extrapolation should be considered with caution as multiple cell lines must always be used. The hollow fibre assay offers a solution for limiting the number of test animals in xenograft research because of the ability for implanting multiple cell lines in one mouse. There is also a broad range of genetically modified mice engineered to investigate the pathophysiology of HCC. Transgenic mice expressing viral genes, oncogenes and/or growth factors allow the identification of pathways involved in hepatocarcinogenesis.

Angiogenesis in chronic liver disease and its complications

Nowadays, liver cancer, cirrhosis and other liver‐related diseases are the fifth most common cause of mortality in the UK. Furthermore, chronic liver diseases (CLDs) are one of the major causes of death, which are still increasing year‐on‐year. Therefore, knowledge about the pathophysiology of CLDs and its complications is of uttermost importance. The goal of this review is to clarify the role of angiogenesis in the disease progression of various liver diseases. Looking closer at the pathophysiology of portal hypertension (PH), fibrosis, cirrhosis, non‐alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), we find that angiogenesis is a recurring factor in the disease progression. In PH, several factors involved in its pathogenesis, such as hypoxia, oxidative stress, inflammation and shear stress are potential mediators for the angiogenic response. The progression from fibrosis to cirrhosis, the end‐point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. In several stages of NASH, a link might be made between the disease progression and hepatic microvasculature changes. HCC is one of the most vascular solid tumours in which angiogenesis plays an important role in its development, progression and metastasis. The close relationship between the progression of CLDs and angiogenesis emphasises the need for anti‐angiogenic therapy as a tool for blocking or slowing down the disease progression. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs and its complications.

Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with Terlipressin: A retrospective analysis

Abstract Background and Aim: Terlipressin has been proposed to treat renal failure in patients with type 1 hepatorenal syndrome (HRS). However, the predictive factors for improved renal function and survival are unknown in patients with type 1 HRS treated with terlipressin. The aim of the present retrospective study was to investigate the predictive factors and prognosis of patients with type 1 HRS treated with terlipressin.

The value of laparoscopic liver surgery for solid benign hepatic tumors

BackgroundLaparoscopic liver resection (LLR) has gained wide acceptance for various liver resection procedures, mainly for benign diseases. However, only small series have been reported from a few selected centers.MethodsBetween January 2001 and January 2006, a total of 629 liver resections were performed at our institution. The indication was solid benign liver tumor in 56 (8.9%) patients. LLR was performed in 20 (35.7%) cases. Data from the LLR group were compared with those from a consecutive control group undergoing open liver surgery (OS) for similar indications in a matched-pair analysis during the same period. The pairs were matched as closely as possible for age, gender, American Society of Anesthesiologists (ASA) score, indication for resection, and type and location of the lesions. The endpoint was to investigate overall morbidity and outcome.ResultsAll patients but one are alive and well after a mean follow-up of 35 months (range 10–60 months). Conversion laparotomy was required in two out of 20 (10%) cases for uncontrolled bleeding (one requiring temporary hemodialysis). LLR was characterized by faster time to first oral intake and shorter hospital stay compared to OS (p = 0.001 and 0.008, respectively). Incisional hernias (25%) were only recorded in the OS (p = 0.047 vs. LLR). Overall morbidity was 45% in OS versus 20% in LLR (p = 0.3).ConclusionsLLR significantly reduced time to oral intake, hospital stay, and incisional hernias compared to OS. Bleeding is a major risk and should be carefully considered when resecting benign tumors. In the hands of expert surgeons, LLR may become the gold standard for the resection of benign liver tumors located in the anterior and lateral sectors and for minor hepatic resections.

Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial.

BACKGROUND & AIMS Severe acute alcoholic hepatitis is associated with a high mortality rate. Oxidative stress is involved in the pathogenesis of acute alcoholic hepatitis. Previous findings had also suggested that enteral nutritional support might increase survival in patients with severe acute alcoholic hepatitis. Therefore, the aim of the present study was to evaluate the efficacy of N-acetylcysteine in combination with adequate nutritional support in patients with severe acute alcoholic hepatitis. METHODS Patients with biopsy-proven acute alcoholic hepatitis and mDF ≥32 were randomized to receive N-acetylcysteine intravenously or a placebo perfusion along with adequate nutritional support for 14 days. The primary endpoint was 6-month survival; secondary endpoints were biological parameter evolution and infection rate. RESULTS Fifty-two patients were randomized in the study (28 into the N-acetylcysteine arm, 24 into the control arm), and among them, five were excluded from the analysis for protocol violation. The two groups did not differ in baseline characteristics. Survival rates at 1 and 6 months in N-acetylcysteine and control groups were 70.2 vs. 83.8% (p=0.26) and 62.4 vs. 67.1% (p=0.60), respectively. Early biological changes, documented infection rate at 1 month, and incidence of hepatorenal syndrome did not differ between the two groups. CONCLUSIONS In this study, high doses of intravenous N-acetylcysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe acute alcoholic hepatitis patients with adequate nutritional support. However, these results must be viewed with caution, since the study suffered from a lack of power.

Inhibition of Placental Growth Factor Activity Reduces the Severity of Fibrosis, Inflammation, and Portal Hypertension in Cirrhotic Mice

Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. Anti‐PlGF is therefore currently being clinically evaluated for the treatment of cancer patients. In cirrhosis, hepatic fibrogenesis is accompanied by extensive angiogenesis. In this paper, we evaluated the pathophysiological role of PlGF and the therapeutic potential of anti‐PlGF in liver cirrhosis. PlGF was significantly up‐regulated in the CCl4‐induced rodent model of liver cirrhosis as well as in cirrhotic patients. Compared with wild‐type animals, cirrhotic PlGF−/− mice showed a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension. Importantly, pharmacological inhibition with anti‐PlGF antibodies yielded similar results as genetic loss of PlGF. Notably, PlGF treatment of activated hepatic stellate cells induced sustained extracellular signal‐regulated kinase 1/2 phosphorylation, as well as chemotaxis and proliferation, indicating a previously unrecognized profibrogenic role of PlGF. Conclusion: PlGF is a disease‐candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile. (HEPATOLOGY 2011;)

The HCV serum proteome: a search for fibrosis protein markers.

Summary.  Liver fibrosis/cirrhosis is a serious health issue in hepatitis C virus (HCV‐) infected patients and is currently diagnosed by the invasive liver biopsy. The aim of this study was to find useful fibrosis markers in HCV‐patients’ sera of different fibrosis degrees (METAVIR F0‐F4) based on proteomics. Serum proteome profiles were created by two‐dimensional gel electrophoresis. Profiles were analysed between different degrees of fibrosis (F0‐F4) and between early (F0F1) and late (F2F3F4) fibrosis by univariate analyses (P ≤ 0.05). Differentially expressed proteins were subsequently identified by mass spectrometry. Mac‐2‐binding protein, α‐2‐macroglobulin and hemopexin were increased in F4 opposite F0/F1. A‐1‐antitrypsin, leucine‐rich α‐2‐glycoprotein and fetuin‐A were decreased in F4 opposite F0/F1. Late fibrosis was characterized by an increase in Mac‐2‐binding protein, α‐2‐macroglobulin and α‐1B‐glycoprotein expression and a decrease in haptoglobin expression. Mac‐2‐binding protein expression was confirmed by dot blot assay and enzyme‐linked immunosorbent assay in a secondary population. In conclusion, serum proteome analysis enabled the detection/identification of existing and new candidate markers in line with fibrosis progression in HCV‐patients.

Increased angiogenesis and permeability in the mesenteric microvasculature of rats with cirrhosis and portal hypertension: an in vivo study

Abstract: Background: In vivo evidence for angiogenesis in the splanchnic vasodilation in portal hypertension (PHT) and cirrhosis is lacking. Vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) are mediators of angiogenesis. The present study visualises in vivo structural changes (angiogenesis and vascular hyperpermeability) and examines the presence of VEGF and eNOS in the mesenteric microvasculature of animal models of PHT with and without cirrhosis.