The hedgehog inhibitor cyclopamine reduces β-catenin-Tcf transcriptional activity, induces E-cadherin expression, and reduces invasion in colorectal cancer cells

© 2015 by the authors; licensee MDPI, Basel, Switzerland. Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer

Pleurobiliary fistula, a rare complication of hepatocellular carcinoma after locoregional chemotherapy: a case report

A rare complication of the compilation of high intrahepatic biliary pressure and the formation of a subdiaphragmatic abscess is that of pleurobiliary fistula. We present a case of 67-year-old male who presented with pleurobiliary fistula following transarterial chemoembolization in a patient with a large hepatocellular carcinoma, as well as the course of the diagnostic procedures and the therapeutics interventions which took place

Spontaneous regression of a true splenic cyst: a case report and review of the literature

Splenic cysts are rare clinical findings, detected due to derivative symptoms or as a random discovery in abdominal imaging. Although there still remains controversy as to their optimal treatment, bigger secondary cysts should be treated surgically. However, spontaneous regression may be observed in cysts with a diameter smaller than 4 cm. In these cases, expectant treatment is preferable. We report, herein, a single case of a splenic cyst in an adult woman, who reported minor symptoms despite the size of the lesion and who demonstrated a possible almost total regression of the cyst within a ten-year period, accompanying with review of the most recent literature

Diffuse anorectal melanoma; review of the current diagnostic and treatment aspects based on a case report

Primary anorectal melanoma is a rare and aggressive disease. Patients commonly complain for changes in bowel habits and rectal bleeding, and proctoscopically they mostly appear as non pigmented or lightly pigmented polypoid lesions. Such a lesion should always raise a high index of suspicion in any gastroenterologist or surgeon to prompt surgery, since early radical excision is the only treatment option

BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells

To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently, B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be overexpressed in a subset of colorectal cancers (CRCs), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin, it is perhaps surprising, given the importance of deregulated Wnt/β-catenin/T-cell factor (TCF) signalling in colorectal carcinogenesis, that the functional significance of this interaction is not known. Here, we show for the first time that BCL-3 acts as a co-activator of β-catenin/TCF-mediated transcriptional activity in CRC cell lines and that this interaction is important for Wnt-regulated intestinal stem cell gene expression. We demonstrate that targeting BCL-3 expression (using RNA interference) reduced β-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes LGR5 and ASCL2. In contrast, the expression of canonical Wnt targets Myc and cyclin D1 remained unchanged. Furthermore, we show that BCL-3 increases the functional stem cell phenotype, as shown by colorectal spheroid and tumoursphere formation in 3D culture conditions. We propose that BCL-3 acts as a driver of the stem cell phenotype in CRC cells, potentially promoting tumour cell plasticity and therapeutic resistance. As recent reports highlight the limitations of directly targeting cancer stem cells (CSCs), we believe that identifying and targeting drivers of stem cell plasticity have significant potential as new therapeutic targets. This article has an associated First Person interview with the first author of the paper

Surgical treatment of giant mesenteric fibromatosis presenting as a gastrointestinal stromal tumor: a case report

<p>Abstract</p> <p>Introduction</p> <p>Intra-abdominal fibromatosis, usually located at the mesenteric level, is a locally invasive tumor of fibrous origin, with no ability to metastasize, but a tendency to recur. Certain non-typical cases of intra-abdominal fibromatosis with involvement of the bowel wall can be misdiagnosed because of their different biological behavior.</p> <p>Case presentation</p> <p>We describe the case of a 64-year-old Caucasian man presenting with mesenteric fibromatosis and involvement of the bowel wall, who was treated surgically. The macroscopic and microscopic appearance of the lesion mimicked a gastrointestinal stromal tumor, a tumor with potential malignant behavior.</p> <p>Conclusion</p> <p>It is essential to make an early and correct diagnosis in such equivocal cases, so that the appropriate treatment can be chosen and suitable patients admitted to clinical trials if appropriate. New and reliable criteria for discriminating between intra-abdominal fibromatosis and gastrointestinal stromal tumor should be proposed and established because novel sophisticated therapeutic strategies have been introduced in the international literature.</p

BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling

Objective Colorectal cancer remains the fourth most common cause of cancer-related mortality worldwide. Here we investigate the role of nuclear factor-?B (NF-?B) co-factor B-cell CLL/lymphoma 3 (BCL-3) in promoting colorectal tumour cell survival. Design Immunohistochemistry was carried out on 47 tumour samples and normal tissue from resection margins. The role of BCL-3/NF-?B complexes on cell growth was studied in vivo and in vitro using an siRNA approach and exogenous BCL-3 expression in colorectal adenoma and carcinoma cells. The question whether BCL-3 activated the AKT/protein kinase B (PKB) pathway in colorectal tumour cells was addressed by western blotting and confocal microscopy, and the ability of 5- aminosalicylic acid (5-ASA) to suppress BCL-3 expression was also investigated. Results We report increased BCL-3 expression in human colorectal cancers and demonstrate that BCL-3 expression promotes tumour cell survival in vitro and tumour growth in mouse xenografts in vivo, dependent on interaction with NF-?B p50 or p52 homodimers. We show that BCL-3 promotes cell survival under conditions relevant to the tumour microenvironment, protecting both colorectal adenoma and carcinoma cells from apoptosis via activation of the AKT survival pathway: AKT activation is mediated via both PI3K and mammalian target of rapamycin (mTOR) pathways, leading to phosphorylation of downstream targets GSK- 3 and FoxO1/3a. Treatment with 5-ASA suppressed BCL-3 expression in colorectal cancer cells. Conclusions Our study helps to unravel the mechanism by which BCL-3 is linked to poor prognosis in colorectal cancer; we suggest that targeting BCL-3 activity represents an exciting therapeutic opportunity potentially increasing the sensitivity of tumour cells to conventional therapy

Obstructive Jaundice in Polycystic Liver Disease Related to Coexisting Cholangiocarcinoma

Although jaundice rarely complicates polycystic liver disease (PLD), secondary benign or malignant causes cannot be excluded. In a 72-year-old female who presented with increased abdominal girth, dyspnea, weight loss and jaundice, ultrasound and computed tomography confirmed the diagnosis of PLD by demonstrating large liver cysts causing extrahepatic bile duct compression. Percutaneous cyst aspiration failed to relief jaundice due to distal bile duct cholangiocarcinoma, suspected by magnetic resonance cholangiopancreatography (MRCP) and confirmed by endoscopic retrograde cholangiopancreatography (ERCP). Coexistence of PLD with distal common bile duct cholangiocarcinoma has not been reported so far