ß-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra- and extrahepatic bile ducts. Until now, no effective medical therapy exists. To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the ß-adrenoceptors, we used the Mdr2(-/-) mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2(-/-) mice untreated or treated with the ß-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for α-smooth muscle actin (α-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-ß, TNF-α, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2(-/-) mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2(-/-) mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the ß-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-α, TGF-ß, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis. Therefore, the blockade of ß-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.

Neighbor of Punc E11, a novel oncofetal marker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the 5th common malignancy worldwide, but established markers fail to detect up to one third of HCC. We have recently identified Neighbor of Punc E11 (Nope) as a surface marker for murine fetal liver stem cells. Similar to commonly used HCC markers such as α-Fetoprotein (Afp) and Glypican-3 (Gpc-3), we here establish Nope as an oncofetal marker of murine and human HCC and investigate its specific expression in hepatoma cell lines and primary HCC. Murine and human hepatoma cell lines and Cre-inducible SV40 T-antigen transgenic mice (Alb-SV40TAg(ind) ) were analyzed for Nope expression in comparison to common HCC markers by quantitative RT-PCR, Western blot analyses and immunohistochemistry. Nope expression in primary human HCC was investigated using Oncomine Microarray database. Nope expression was elevated in 8 of 10 investigated murine and human hepatoma cell lines and in all tumors of our oncogenic mouse model but remained undetectable in normal liver and at preneoplastic stages of murine hepatocarcinogenesis. Furthermore, a significant induction of Nope was detected in primary human cancers compared to corresponding normal or cirrhotic tissue. Nope expression in tumor specimens and murine cell lines correlated closely with expression levels of Gpc-3, whereas expression levels of Afp showed high variations. In conclusion, we identified Nope as a novel oncofetal surface marker for murine and human HCC. Nope is specifically expressed by epithelial tumor cells but not in preneoplastic stages and is a promising marker for clinical application because of its high detection rate in Afp-positive and Afp-negative tumors.

The role of microRNAs in primary liver cancer.

Small RNA molecules such as microRNAs, for many years considered to be superfluous genomic material, are now known to play important regulatory roles in apoptosis, cell proliferation and differentiation, angiogenesis and thus in carcinogenesis. Primary liver carcinomas such as hepatocellular carcinomas, cholangiocarcinomas and mixed variants show a rising incidence with high mortality among affected patients but lack effective targeted therapies except the new multiple kinase inhibitor Sorafenib. This review elucidates the recent contributions of miRNA gene expression analyses to a better understanding of the complex molecular interactions in liver carcinogenesis and highlights their future promise to provide novel tools for improved diagnostics, more accurate prognostic assessment and tailored molecular therapies in liver cancer.

MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma.

UNLABELLED: MicroRNAs are small noncoding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) through translational repression or RNA degradation. Many fundamental biological processes are modulated by microRNAs, and an important role for microRNAs in carcinogenesis is emerging. Because understanding the pathogenesis of viral-associated hepatocellular carcinomas is important in developing effective means of classification, prognosis, and therapy, we examined the microRNA expression profiles in a large set of 52 human primary liver tumors consisting of premalignant dysplastic liver nodules and hepatocellular carcinomas by quantitative real-time polymerase chain reaction. All patients were infected with hepatitis C, and most had liver cirrhosis. Initially, the accessibility of microRNAs from formalin-fixed paraffin-embedded archival liver tissue by real-time polymerase chain reaction assays was shown. Subsequently, target parenchyma from routinely processed tissue was macrodissected, RNA was extracted, and reverse transcription followed by quantitative real-time polymerase chain reaction was performed. Relative quantification was performed by the 2(-DeltaDeltaCt) method with normal livers as a calibrator. In order to obtain a comprehensive microRNA gene expression profile, 80 microRNAs were examined in a subset of tumors, which yielded 10 up-regulated and 19 down-regulated microRNAs compared to normal liver. Subsequently, five microRNAs (miR-122, miR-100, miR-10a, miR-198, and miR-145) were selected on the basis of the initial results and further examined in an extended tumor sample set of 43 hepatocellular carcinomas and 9 dysplastic nodules. miR-122, miR-100, and miR-10a were overexpressed whereas miR-198 and miR-145 were up to 5-fold down-regulated in hepatic tumors compared to normal liver parenchyma. CONCLUSION: A subset of microRNAs are aberrantly expressed in primary liver tumors, serving both as putative tumor suppressors and as oncogenic regulators.

Giant polypoid gastric heterotopia of the jejunum presenting with intermittent intussusception.

We report the case of a 17-year-old female with symptoms of intermittent small bowel obstruction. Computed tomography scan of the abdomen revealed an intussusception. The patient underwent a laparoscopic-assisted resection of the mass, which proved to be gastric heterotopia of the jejunum. We report on the case, discuss the surgical approach, and review the pertinent literature.

Fallopian tube prolapse mimicking aggressive angiomyxoma.

A 68-year-old woman presented with a 4-cm polypoid bleeding mass protruding from the vaginal apex 30 years after vaginal hysterectomy. Laparotomy did not confirm the clinical suspicion of bowel prolapse and led to resection of the mass. Microscopic examination revealed a hypocellular edematous lesion with glandular areas resembling fallopian tube epithelium. Condensation of eosinophilic fibrils around medium sized vessels was marked. This case of fallopian tube prolapse shows an unusual resemblance of aggressive angiomyxoma and thus poses a diagnostic pitfall.

Glucagon-like peptide 2 is an endogenous mediator of postresection intestinal adaptation.

BACKGROUND: After massive small bowel resection, the remnant intestine undergoes compensatory adaptation. We tested the hypothesis that glucagon-like peptide-2 (GLP-2) is an endogenous mediator of postresection intestinal adaptation. METHODS: Rats were allocated to 1 of 4 groups: groups 1 and 2 rats underwent mid-small bowel transection and reanastomosis; groups 3 and 4 rats underwent 75% mid-small bowel resection and reanastomosis. Groups 2 and 4 rats were administered 1.8 mg of antirat GLP-2 antibody twice daily beginning immediately after the surgical procedure; groups 1 and 3 rats were administered rabbit serum (control). Ileal specimens were harvested on postoperative day 7. RESULTS: Ileal mucosa from group 3 animals displayed morphologic and proliferative indices of adaptation. Each of these indices of adaptation was inhibited by GLP-2 immunoneutralization (group 4). Morphologic and proliferative parameters in the ileum from animals that had undergone transection with reanastomosis were unaffected by GLP-2 immunoneutralization. CONCLUSIONS: These results suggest that GLP-2 is an endogenous mediator of postresection intestinal adaptation.

Pulmonary capillary hemangiomatosis arising in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant inherited disease characterized by epistaxis, telangiectases, and visceral arteriovenous malformations that can lead to hemorrhage and other complications. We report the case of a 56-year-old female patient with HHT and pulmonary hypertension who died with intractable pulmonary and gastrointestinal bleeding. Autopsy revealed vascular malformations in the lungs, gastrointestinal tract, liver, spleen, and brain. Capillary proliferations in the pulmonary alveolar walls, characteristic of pulmonary capillary hemangiomatosis, were identified, as was evidence of pulmonary hypertensive arteriopathy. To our knowledge, this is the first report of pulmonary capillary hemangiomatosis arising in HHT. The histopathologic findings of HHT and pulmonary capillary hemangiomatosis are reviewed, and a possible role for diminished capillary expression of endothelial nitric oxide synthase is discussed.

Gene expression profiles of human breast cancer progression.

Although distinct pathological stages of breast cancer have been described, the molecular differences among these stages are largely unknown. Here, through the combined use of laser capture microdissection and DNA microarrays, we have generated in situ gene expression profiles of the premalignant, preinvasive, and invasive stages of human breast cancer. Our data reveal extensive similarities at the transcriptome level among the distinct stages of progression and suggest that gene expression alterations conferring the potential for invasive growth are already present in the preinvasive stages. In contrast to tumor stage, different tumor grades are associated with distinct gene expression signatures. Furthermore, a subset of genes associated with high tumor grade is quantitatively correlated with the transition from preinvasive to invasive growth.

Biliary adenofibroma: a rare neoplasm of bile duct origin with an indolent behavior.

We report a case of biliary adenofibroma in a 47-year-old woman, who presented with right upper quadrant pain for several months. Abdominal imaging revealed a 16-cm solid and cystic mass in the left hepatic lobe. Histologically, the tumor showed two distinct components: 1) cystic and tubular structures lined by low columnar to cuboidal biliary-type epithelium, and 2) a dense fibrous stroma composed of spindle-shaped cells with only mild nuclear pleomorphism and inconspicuous nucleoli. Mitoses and stromal invasion were absent. The glandular epithelium stained positively for keratin AE.3/Cam 5.2, cytokeratin 7, cytokeratin 19, carcinoembryonic antigen, and epithelial membrane antigen and had a low Ki-67 proliferative index. In addition, the epithelium was positive for D10 but did not stain for 1F6 or acid mucin with alcian blue stain. This staining pattern, similar to bile duct hamartoma (von Meyenburg complex) with which this tumor shares morphologic similarity, suggests that biliary adenofibroma originates from interlobular or larger bile ducts. Three years after a subtotal resection no metastasis or significant tumor growth was noted. However, given the marked nuclear p53 immunoreactivity and tetraploidy status observed in this tumor, we cannot exclude that biliary adenofibroma may represent a premalignant process that warrants complete resection and thorough histopathologic examination.