Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC.

Background And Aims: HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch.

Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.

Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC.

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

Background & Aims: Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice.

Knockdown of Atg7 Induces Nuclear-LC3 Dependent Apoptosis and Augments Chemotherapy in Colorectal Cancer Cells.

Autophagy is a catabolic process that enables cells to degrade obsolete content and refuel energy depots. In colorectal cancer (CRC) autophagy has been shown to promote tumorigenesis through energy delivery in the condition of uncontrolled proliferation. With this study, we aimed at evaluating whether autophagy sustains CRC cell viability and if it impacts therapy resistance.

A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.

Background: Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.

Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression.

Background/aim: Sorafenib leads to improved survival in advanced hepatocellular carcinoma (HCC) patients. Continuation of sorafenib beyond progression has been a possible treatment strategy when further approved therapeutic agents are lacking.

Methods: We performed a retrospective analysis of all HCC patients at our institution with documented disease progression under treatment with sorafenib.

Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice.

Background & Aims: Cholangiocyte proliferation and ductular reaction contribute to the onset and progression of liver diseases. Little is known about the role of the transcription factor nuclear factor-κB (NF-κB) in this process. We investigated the activities of the RELB proto-oncogene NF-κB subunit in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction.

Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer.

Purpose: Recent studies have emphasized a key role for the anti-apoptotic Bcl-2 family member Mcl-1 in conferring tumor cell survival and drug resistance in breast cancer (BC). Mcl-1 inhibitors, such as the BH3-mimetic EU-5346, therefore represent an exciting new class of targeting agents and are a current focus of widespread cancer-drug development efforts.

Methods: ONCOMINE analysis was utilized to compare expression profiles of Bcl-2 family members across all major BC subgroups.

An undifferentiated carcinoma at Klatskin-position with long-term complete remission after chemotherapy.

Background: Neoplasms anatomically adjacent to the bile duct usually derive from malignantly transformed cholangiocytes forming cholangiocarcinoma (CCA). CCAs are divided in extrahepatic (eCCA) and intrahepatic (iCCA) tumors. Patients with irresectable CCAs are treated with systemic chemotherapy and have an unfavorable prognosis with a median survival of about one year.

Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas.

Background: Changes in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).

Patients And Methods: Forty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12-1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.

PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study.

Background: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer.

Patients And Methods: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m and gemcitabine 1000 mg/m on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.

Liver cancers with stem/progenitor-cell features - a rare chemotherapy-sensitive malignancy.

Primary liver tumors are a heterogeneous group of malignancies. Besides classical hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), combined and intermediate forms of liver cancer exist and can express stem-cell markers like nuclear cell adhesion molecule (NCAM-1/CD56), c-kit (CD117) or epithelial cell adhesion molecule (EpCAM) together with high proliferative activity. Liver tumors with progenitor-cell features are associated with an unfavorable prognosis, but the phenotype has not resulted in therapeutic consequences so far.

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur.

Activation of silent mating type information regulation 2 homolog 1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation.

Unlabelled: Incidence and prevalence of inflammatory liver diseases has increased over the last years, but therapeutic options are limited. Pregnancy induces a state of immune tolerance, which can result in spontaneous improvement of clinical symptoms of certain autoimmune diseases including autoimmune hepatitis (AIH). We investigated the immune-suppressive mechanisms of the human pregnancy hormone, chorionic gonadotropin (hCG), in the liver.

Possible Mechanisms of Ethanol-Mediated Colorectal Carcinogenesis: The Role of Cytochrome P4502E1, Etheno-DNA Adducts, and the Anti-Apoptotic Protein Mcl-1.

Background: Chronic alcohol consumption is a risk factor for colorectal cancer. The mechanisms by which ethanol (EtOH) exerts its carcinogenic effect on the colorectal mucosa are not clear and may include oxidative stress with the action of reactive oxygen species (ROS) generated through EtOH metabolism via cytochrome P4502E1 (CYP2E1) leading to carcinogenic etheno-DNA adducts. ROS may also induce apoptosis.

Bcl-xL is an oncogenic driver in colorectal cancer.

Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells.

Prolyl Hydroxylase 3 Attenuates MCL-1-Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells.

Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer.

Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications.

Background: Molecular mechanisms leading to the adaptation of breast cancer (BC) cells to hypoxia are largely unknown. The anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) is frequently amplified in BC; and elevated Mcl-1 levels have been correlated with poor prognosis. Here we investigated the pathophysiologic role of Mcl-1 in Her2-positive BC cells under hypoxic conditions.

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach.

Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis.

Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling.

Background: Colorectal cancer is the third most common malignancy in humans and novel therapeutic approaches are urgently needed. Autophagy is an evolutionarily highly conserved cellular process by which cells collect unnecessary organelles or misfolded proteins and subsequently degrade them in vesicular structures in order to refuel cells with energy. Dysregulation of the complex autophagy signaling network has been shown to contribute to the onset and progression of cancer in various models.

CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes.

Aim: To analyze the role of CYLD for receptor-mediated cell death of murine hepatocytes in acute liver injury models.

Methods: Hepatocyte cell death in CYLD knockout mice (CYLD(-/-) ) was analyzed by application of liver injury models for CD95- (Jo2) and tumor necrosis factor (TNF)-α- [D-GalN/lipopolysaccharide (LPS)] induced apoptosis. Liver injury was assessed by measurement of serum transaminases and histological analysis.

Hepatobiliary malignancies in Wilson disease.

Backgrounds & Aims: Reports of hepatobiliary malignancies in Wilson disease are sparse. The aim of this study was to evaluate hepatobiliary malignancies in Wilson disease patients concerning the clinical course of tumour disease and pathological analysis of tumour tissue.

Methods: Multicenter cohort study of patients with confirmed diagnosis of Wilson disease treated at the Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, the university hospitals Heidelberg, Duesseldorf and Dresden, Germany, and the Department of Hepatology, University Leuven, Belgium.

Nuclear expression of the deubiquitinase CYLD is associated with improved survival in human hepatocellular carcinoma.

Background & Aims: The deubiquitinase CYLD removes (K-63)-linked polyubiquitin chains from proteins involved in NF-κB, Wnt/ß-catenin and Bcl-3 signaling. Reduced CYLD expression has been reported in different tumor entities, including hepatocellular carcinoma (HCC). Furthermore, loss of CYLD has been shown to contribute to HCC development in knockout animal models.

Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients.

Background & Aims: The BCLC-staging system is used to facilitate treatment decisions in patients with hepatocellular carcinoma (HCC). Owing to the observed clinical heterogeneity of the intermediate stage BCLC-B, a subclassification was proposed taking Child-Pugh score and extended criteria for transplantation into account. Analysis of the prognostic significance of a proposed subclassification of the BCLC-B score in a European cohort of HCC patients.