Genetic approaches to the therapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a devastating malignancy originating from hepatocytes. There is an urgent need for novel therapeutic approaches. Currently explored gene therapy systems have not yet achieved significant survival benefits. The aim of this thesis was the development and evaluation of novel genetic approaches to this malignancy. The results of this thesis show that the only non-conjugated gene delivery system achieving significant intratumoral transgene expression is direct injection. Systemic gene delivery systems based upon Tf-shielded, polyethylenimine (PEI) based polyplexes and stabilized plasmid lipid particles (SPLP) do achieve efficient intratumoral transgene expression levels comparable to direct intratumoral injection, but their use is limited by their low intratumoral biodistribution. Further, this study shows that the use of non-viral replicon vectors based on the autonomously replicating parvoviruses minute virus of mice (pMVM) is feasible. In contrast to its viral equivalent, it allows expansion of its genome size to >106% and avoids immunogenicity. It maintains its tumorselectivity, but loses its cytotoxicity. The results of this thesis show that the Edmonston strain of measles virus (MV-Edm) efficiently infects human HCC cell lines resulting in syncytia formation followed by apoptotic cell death. The use of recombinant MV-Edm expressing marker genes allows non-invasive tracking of MV-Edm infection and kinetics. Treatment of mice bearing subcutaneous human HCC xenografts with recombinant MV-Edm resulted in significant survival benefits and tumor regression in up to one third of animals

Oxidative stress via hydrogen peroxide and menadione does not induce the secretion of IGFBP-5 in primary rat hepatocytes

Conference abstract describing how oxidative stress via hydrogen peroxide and menadione does not induce the secretion of IGFBP-5 in primary rat hepatocytes. Presented at the 2010 annual congress of the british toxicology societ

Cancer review: Cholangiocarcinoma

Cholangiocarcinoma (CCA) is the most common biliary tract malignancy. CCA is classified as intrahepatic, perihilar or distal extrahepatic; the individual subtypes differ in their biologic behavior, clinical presentation, and management. Throughout the last decades, CCA incidence rates had significantly increased. In addition to known established risk factors, novel possible risk factors (i.e. obesity, hepatitis C virus) have been identified that are of high importance in developed countries where CCA prevalence rates have been low. CCA tends to develop on the background of inflammation and cholestasis. In recent years, our understanding of the molecular mechanisms of cholangiocarcinogenesis has increased, thereby, providing the basis for molecularly targeted therapies. In its diagnostic evaluation, imaging techniques have improved, and the role of complementary techniques has been defined. There is a need for improved CCA biomarkers as currently used ones are suboptimal. Multiple staging systems have been developed, but none of these is optimal. The prognosis of CCA is considered dismal. However, treatment options have improved throughout the last two decades for carefully selected subgroups of CCA patients. Perihilar CCA can now be treated with orthotopic liver transplantation with neoadjuvant chemoradiation achieving 5-year survival rates of 68%. Classically considered chemotherapy-resistant, the ABC-02 trial has shown the therapeutic benefit of combination therapy with gemcitabine and cisplatin. The benefits of adjuvant treatments for resectable CCA, local ablative therapies and molecularly targeted therapies still need to be defined. In this article, we will provide the reader with an overview over CCA, and discuss the latest developments and controversies

A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells.

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that, failing to kill CCA cells, instead promotes their tumorigenicity and especially the metastatic behaviors of cell migration and invasion. Second mitochondria-derived activator of caspase (smac) mimetics are promising cancer therapeutic agents that enhance proapoptotic death receptor signaling by causing cellular degradation of inhibitor of apoptosis (IAP) proteins. Our aim was to examine the in vitro and in vivo effects of the smac mimetic JP1584 in CCA. Despite JP1584-mediated loss of cellular inhibitor of apoptosis-1 (cIAP-1) and cIAP-2, TRAIL failed to induce apoptosis in KMCH-1, TFK-1, and BDEneu CCA cells; a finding consistent with a downstream block in death signaling. Because cIAP-1 and cIAP-2 also promote nuclear factor kappa B (NF-kappaB) activation by the canonical pathway, the effect of JP1584 on this signaling pathway was examined. Treatment with JP1584 inhibited TRAIL-induced NF-kappaB activation as well as TRAIL-mediated up-regulation of the NF-kappaB target gene, matrix metalloproteinase 7 (MMP7). JP1584 also reduced TRAIL-mediated CCA cell migration and invasion in vitro. Finally, in a syngeneic rat orthotopic CCA model, JP1584 administration reduced MMP7 messenger RNA levels and extrahepatic metastases. CONCLUSION: : Although the smac mimetic JP1584 does not sensitize cells to apoptosis, it reduces TRAIL-induced CCA cell metastatic behavior. These data support the emerging concept that IAPs are prometastatic and represent targets for antimetastatic therapies

The true prognosis of resected distal cholangiocarcinoma

International audienceBACKGROUND: Prognosis of distal cholangiocarcinoma (DCC) after pancreaticoduodenectomy (PD) remains poorly assessed. The aims of this study were to describe the oncological results of PD in DCC and to compare its prognosis to pancreatic ductal adenocarcinoma (PDAC). METHODS: All PD for periampullary carcinoma performed between January 2000 and March 2013 were extracted from a prospective database. Risk factors likely to influence overall (OS) and disease-free (DFS) survivals of DCC were assessed by multivariable analyses. The DCC and PDAC prognoses were compared after matching using propensity score (nearest neighbor matching). RESULTS: Of the 290 patients analyzed, 56 had DCC, with a mean age of 65 ± 15 years. The median OS was 36.9 months. Recurrence occurred in 35 patients (67%), mostly in the liver (37%). The median DFS was 14.6 months. Combined organ resection was an independent risk factor for worse OS and DFS (P = 0.01 and P = 0.001, respectively). Matching analysis found no significant difference between DCC and PDAC in terms of OS (P = 0.284) or DFS (P = 0.438). CONCLUSION: This first propensity analysis demonstrated that DCC and PDAC have the same prognosis, linked to the high rate of early recurrence, particularly associated with the need for combined organ resection. J. Surg. Oncol. © 2016 Wiley Periodicals, In

Metastasis-associated in colon cancer 1 is an independent prognostic biomarker for survival in klatskin tumor patients

Curative treatment of intrahepatic cholangiocarcinoma (ICC) and hilar cholangiocarcinoma (Klatskin tumors) is limited to surgical resection or orthotopic liver transplantation. However, not all patients benefit from a surgical approach and suffer from early tumor recurrence. Response to chemotherapy is generally poor and, until today, no targeted therapy could be established. Metastasis-associated in colon cancer 1 (MACC1) is a recently discovered regulator of the hepatocyte growth factor (HGF)/Met/mitogen-activated protein kinase pathway, which induces proliferation, migration, and invasion in cell culture, as well as metastasis in mice. MACC1 expression shows a significant correlation with Met expression in colon cancer tissue and is highly prognostic for occurrence of distant metastasis and survival in colon cancer patients. Thus, we aimed to measure the expression of MACC1, Met, and HGF messenger RNA in microdissected tumor tissue and corresponding normal liver tissue of 156 patients with Klatskin tumors (n = 76) and ICC (n = 80) using real-time quantitative reverse-transcriptase polymerase chain reaction. We used immunohistochemical staining to validate the results. MACC1 expression in tumor tissue of both tumor entities was significantly higher than in corresponding normal liver tissue (P < 0.001). Klatskin tumor patients with a history of tumor recurrence had significantly higher MACC1 expression than those without tumor recurrence (P = 0.005). Uni- und multivariate survival analysis showed that Klatskin tumor patients with high MACC1 had a significantly shorter overall (OS) and disease-free survival (DFS; P = 0.001 and P < 0.001, respectively). The multivariate analysis confirmed MACC1 to be an independent factor for overall survival in Klatskin tumor patients (hazard ratio: 2.777; 95% confidence interval: 1.389-5.555; P = 0.004). Conclusion: Our study identified MACC1 as a highly prognostic biomarker for OS and DFS in Klatskin tumor patients. MACC1 expression could become an important diagnostic tool and might be a candidate for targeted therapy

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

Bile duct cells and hepatocytes differentiate from the same hepatic progenitor cells. To investigate the possible association of viral hepatitis B and C with intrahepatic cholangiocarcinoma (ICC), we conducted a retrospective case–control study using univariate and multivariate logistic analyses to identify risk factors for ICC. Besides hepatic lithiasis (25.6%; P<0.001), seropositivity for hepatitis B surface antigen (37.5% of all ICC patients; odds ratio (OR) =4.985, P<0.001) and seropositivity for hepatitis C antibodies (13.1%; OR=2.709; P=0.021) are the primary independent risk factors for ICC. Cirrhosis exerted synergic effects on the development of ICC. We compared the age distributions of viral-hepatitis associated ICC to that of viral hepatitis-associated hepatocellular carcinoma (HCC). The mean age of ICC patients with viral hepatitis B (56.4±11.1 years) were 9 years younger than that of ICC patients with viral hepatitis C (65.6±9.17 years), similar to that observed in HCC. The incidence ratio of HCC : ICC : CHC (combined hepatocellular cholangiocarcinoma) in our population was 233 : 17 : 1 consistent with the theoretic ratio of hepatocyte number to cholangiocyte number in the liver. Our findings indicated that both viral hepatitis-associated ICC and HCC shared common disease process for carcinogenesis and, possibly, both arose from the hepatic progenitor cells

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions

Descriptive Epidemiology of Cholangiocarcinoma and Clonorchiasis in Korea

In 2009, infection with the liver fluke Clonorchis sinensis (C. sinensis) was classified as "carcinogenic to humans" (Group 1) based on its involvement in the etiology of cholangiocarcinoma by the International Agency for Research on Cancer. However, little is known about the descriptive epidemiology of cholangiocarcinoma in Korea. We examined incidence trends of intrahepatic and extrahepatic cholangiocarcinomas, using data from the Korea National Cancer Incidence database for 1999-2005. The prevalence of C. sinensis infection was estimated from a recent population-based survey in rural endemic areas. Cholangiocarcinoma incidence rates are currently rising, even while primary liver cancer incidence rates are decreasing. Annual percent changes in cholangiocarcinoma incidence rates were 8% for males and 11% in females. Known areas of C. sinensis endemicity showed high incidence rates of cholangiocarcinoma. The positivity of C. sinensis eggs in stool samples from endemic areas was more than 25% of adults tested during 2005-2008. From a meta-analysis, the summary odds ratio for cholangiocarcinoma due to C. sinensis infection was 4.7 (95% confidence interval: 2.2-9.8). Approximately 10% of cholangiocarcinomas in Korea were caused by chronic C. sinensis infections. More specific policies, including health education and an extensive effort for early detection in endemic areas, are needed