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Journal of Pathology

Catherine G Fischer, Laura D Wood
Pancreatic cancer arises from non-invasive precursor lesions, including pan creatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), which are curable if detected early enough. Recently, these types of precursor lesions have been extensively characterized at the molecular level, defining the timing of critical genetic alterations in tumorigenesis pathways. The results of these studies deepen our understanding of tumorigenesis in the pancreas, providing novel insights into tumor initiation and progression...
August 13, 2018: Journal of Pathology
Amy M B McCorry, Maurice B Loughrey, Daniel B Longley, Mark Lawler, Philip D Dunne
The process of epithelial-to-mesenchymal transition (EMT) in cancer is a well-described process whereby epithelial tumour cells undergo molecular/phenotypic changes and transition to a mesenchymal biology. To aid in transcriptional characterisation of this process, gene expression signatures have been developed which attribute a relative EMT score to samples in a given cohort. We demonstrate how such EMT signatures can identify epithelial cell line models with high levels of transition, but also highlight that, unsurprisingly, fibroblast cell lines, which are inherently mesenchymal, have a higher EMT score relative to any epithelial cell line studied...
August 13, 2018: Journal of Pathology
Victor Ljl Thijssen, Yvette Wj Paulis, Patrycja Nowak-Sliwinska, Katrin L Deumelandt, Kayoko Hosaka, Patricia Mmb Soetekouw, Anca M Cimpean, Marius Raica, Patrick Pauwels, Joost J van den Oord, Vivianne Cg Tjan-Heijnen, Mary J Hendrix, Carl-Henrik Heldin, Yihai Cao, Arjan W Griffioen
Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extend tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks...
August 12, 2018: Journal of Pathology
Rong Liu, Peiguo Shi, Zhongmei Zhou, Hailin Zhang, Wei Li, Hong Zhang, Ceshi Chen
Krüpple-like factor 5 (KLF5) is required for the development of the embryo and multiple organs, such as the lung and intestine. KLF5 plays a pro-proliferative and oncogenic role in several carcinomas, including breast cancer. However, its role in normal mammary gland development and oncogenesis has not been elucidated in vivo. In this study, we used mammary gland-specific Klf5 conditional knockout mice derived by mating Klf5-LoxP and MMTV-Cre mice. The genetic ablation of Klf5 suppresses mammary gland ductal elongation and lobuloalveolar formation...
August 12, 2018: Journal of Pathology
Beatriz Paniagua-Torija, Michael Norenberg, Angel Arevalo-Martin, Melissa M Carballosa-Gautam, Yolanda Campos-Martin, Eduardo Molina-Holgado, Daniel Garcia-Ovejero
In vertebrates that regenerate the injured spinal cord, cells at the ependymal region proliferate and coordinate the formation of bridges between the lesion stumps. In mammals, these cells also proliferate profusely around the central canal after spinal cord injury, although their actual contribution to repair is controversial. In humans, however, the central canal disappears from early childhood in the majority of individuals, being substituted by astrocyte gliosis, ependymocyte clusters and perivascular pseudo-rosettes...
August 8, 2018: Journal of Pathology
Elena Rampanelli, Peter Ochodnicky, Johannes P C Vissers, Loes M Butter, Nike Claessen, Alessia Calcagni, Lotte Kors, Lee A Gethings, Stephan J L Bakker, Martin H de Borst, Gerjan J Navis, Gerhard Liebisch, Dave Speijer, Marius A van den Bergh Weerman, Bettina Jung, Jan Aten, Eric Steenbergen, Gerd Schmitz, Andrea Ballabio, Sandrine Florquin, Johannes M F G Aerts, Jaklien C Leemans
Obesity and dyslipidaemia are features of the metabolic syndrome and risk factors for chronic kidney disease. The cellular mechanisms connecting metabolic syndrome with chronic kidney disease onset and progression remain largely unclear. We show that proximal tubular epithelium is a target site for lipid deposition upon overnutrition with a cholesterol-rich Western-type diet. Affected proximal tubule epithelial cells displayed giant vacuoles of lysosomal or autophagosomal origin, harbouring oxidized lipoproteins and concentric membrane layer structures (multilamellar bodies), reminiscent of lysosomal storage diseases; lipidomic analysis revealed renal deposition of cholesterol and phospholipids, including lysosomal phospholipids...
August 2, 2018: Journal of Pathology
Anna Lechado I Terradas, Maurizio Vitadello, Leonardo Traini, Arvind Venkat Namuduri, Stefano Gastaldello, Luisa Gorza
Skeletal muscle atrophy following unloading or immobilization represents a major invalidating event in bedridden patients. Among mechanisms involved in atrophy development, a controversial role is played by neuronal-NOS (nNOS; NOS1) whose dysregulation at the protein level and/or subcellular distribution also characterizes other neuromuscular disorders. This study aimed to investigate unloading-induced changes in nNOS before any evidence of myofiber atrophy, using vastus lateralis biopsies obtained from young healthy subjects after a short bed-rest and rat soleus muscles after exposure to short-unloading periods...
July 31, 2018: Journal of Pathology
Louise van der Weyden, Anneliese O Speak, Agnes Swiatkowska, Simon Clare, Andrea Schejtman, Giorgia Santilli, Mark J Arends, David J Adams
Metastasis is the leading cause of death in cancer patients and successful colonisation of a secondary organ by circulating tumour cells (CTCs) is the rate-limiting step of this process. We used tail-vein injection of B16-F10 melanoma cells into mice to mimic the presence of CTCs and allow for assessment of host (microenvironmental) factors that regulate pulmonary metastatic colonisation. We found that mice deficient for the individual subunits of the NADPH oxidase of myeloid cells, NOX2 (specifically Cyba, Cybb, Ncf1, Ncf2 and Ncf4), all showed decreased pulmonary metastatic colonisation...
July 30, 2018: Journal of Pathology
Enrica Saponara, Michele Visentin, Francesco Baschieri, Gitta Seleznik, Paola Martinelli, Irene Esposito, Johanna Buschmann, Rong Chen, Rossella Parrotta, Nathalie Borgeaud, Marta Bombardo, Ermanno Malagola, Amedeo Caflisch, Hesso Farhan, Rolf Graf, Sabrina Sonda
Pancreatic ductal adenocarcinoma (PDAC), the primary cause of pancreatic cancer mortality, is poorly responsive to currently available interventions. Identifying new targets that drive PDAC formation and progression is critical to develop alternative therapeutic strategies to treat this lethal malignancy. Using genetic and pharmacologic approaches, we investigated in vivo and in vitro whether uptake of the monoamine serotonin is required for PDAC development. We demonstrated that pancreatic acinar cells have the ability to readily take up serotonin in a transport-mediated manner...
July 30, 2018: Journal of Pathology
Erina Iwabuchi, Yasuhiro Miki, Ayako Kanai, Minoru Miyashita, George Kijima, Hisashi Hirakawa, Takashi Suzuki, Takanori Ishida, Hironobu Sasano
Human epidermal growth factor receptor 2 (HER2) is a target of the HER2 inhibitor, trastuzumab, which has been administered to HER2-positive breast cancer patients. However, the therapeutic effects of HER2-inhibitor monotherapy are not always clinically effective compared to its co-treatment with chemotherapy. Therefore, it has become pivotal to predict the therapeutic efficacy of trastuzumab monotherapy prior to administration. Recently, carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) has been reported to be a HER2-related factor...
July 29, 2018: Journal of Pathology
Amy E Vincent, Martin Picard
Mitochondrial diseases are heterogeneous multi-system disorders that present a mosaic pattern of mitochondrial respiratory chain dysfunction. Mitochondrial DNA (mtDNA) mutation load is heterogeneous at multiple levels: across organs, cells, and between sub-cellular compartments. Such heterogeneity poses a diagnostic challenge, but also provides a scientific opportunity to explore the biological mechanisms underlying the onset and progression of these disorders. A recent article in the Journal of Pathology described a novel histochemical technique - NBTx - to quantify mitochondrial cytochrome c oxidase (COX, or complex IV) deficiency...
July 29, 2018: Journal of Pathology
Ya-Yun Chang, Linda Chia-Hui Yu, I-Shing Yu, Yu-Lin Jhuang, Wei-Ju Huang, Ching-Yao Yang, Yung-Ming Jeng
Cadherin-17 is an adhesion molecule expressed specifically in intestinal epithelial cells. It is frequently under-expressed in human colorectal cancer. The physiological function of cadherin-17 and its role in tumorigenesis have not yet been determined. We used the transcription activator-like effector nuclease technique to generate a Cdh17 knockout (KO) mice model. Intestinal tissues were analysed by histological, immunohistochemical, and ultrastructural methods. Colitis was induced by oral administration of dextran sulphate sodium (DSS) and to study effects on intestinal tumorigenesis, mice were given azoxymethane (AOM) and DSS to induce colitis-associated cancer...
July 26, 2018: Journal of Pathology
Thing Rinda Soong, Brooke E Howitt, Alexander Miron, Neil S Horowitz, Frank Campbell, Colleen M Feltmate, Michael G Muto, Ross S Berkowitz, Marisa R Nucci, Wa Xian, Christopher P Crum
The distal Fallopian tube is a site of origin for many "ovarian" high-grade serous carcinomas (HGSCs) with intra-epithelial carcinomas (STICs) that share identical TP53 mutations with metastatic tumors. TP53 mutation-positive early serous proliferations (ESPs) comprise a spectrum including p53 signatures and serous tubal intraepithelial lesions (STILs) and are not considered malignant; however, ESPs are often the only abnormality found in Fallopian tubes of women with metastatic HGSC. The purpose of this study was to determine if a relationship exists between isolated ESPs and concurrent metastatic HGSCs in the absence of STIC...
July 25, 2018: Journal of Pathology
Yun Li, Liwen Deng, Xiaohui Zhao, Bohan Li, Dong Ren, Lihong Yu, Hehai Pan, Qing Gong, Libing Song, Xiang Zhou, Ting Dai
Non-small-cell lung cancer (NSCLC), in which the NF-κB pathway is constitutively activated, is one of the most common malignancies. Herein, we identify an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37), participating in the K63-polyubiquitination of TRAF2, which is a significant step in the activation of NF-κB signaling. Both the mRNA and protein expression levels of TRIM37 were much higher in NSCLC cell lines and tissues than in normal bronchial epithelial cells and matched adjacent non-tumor tissues...
July 25, 2018: Journal of Pathology
Mona Foth, Nur Faezah Binti Ismail, Jeng Sum Charmaine Kung, Darren Tomlinson, Margaret A Knowles, Pontus Eriksson, Gottfrid Sjödahl, Jonathan M Salmond, Owen J Sansom, Tomoko Iwata
Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to Wildtype control mice...
July 25, 2018: Journal of Pathology
Chaoting Zhang, Hongying Huang, Yu Miao, Hongchao Xiong, Zheming Lu
Recent successes in tumour immunotherapies have highlighted importance of tumour immunity. However, most previous studies to date have focused on T cell immune response, although B cells are key players in the core immune network and are associated with T-cell immune response. Based on our previous study delineating T cell receptor (TCR) repertoire in seven patients with esophageal squamous cell carcinoma (ESCC), this study profiled BCR repertoire of multiple tumour regions, adjacent normal tissue and blood from the same seven patients to reveal characteristics of B cell immunity and relationship to TCR repertoire in ESCC patients...
July 20, 2018: Journal of Pathology
Eric Morin, Elin Sjöberg, Vegard Tjomsland, Chiara Testini, Cecilia Lindskog, Oskar Franklin, Malin Sund, Daniel Öhlund, Sara Kiflemariam, Tobias Sjöblom, Lena Claesson-Welsh
Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with Neuropilin-1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation...
July 20, 2018: Journal of Pathology
Sidhant Seth, Ann Ager, Mark Arends, Ian M Frayling
Recent work has provided evidence for genetic and molecular heterogeneity in colorectal cancers (CRCs) arising in patients with Lynch syndrome (LS), dividing these into two groups: G1 and G2. In terms of mutation and gene expression profile, G1 CRCs bear resemblance to sporadic CRCs with microsatellite instability (MSI), whereas G2 CRCs are more similar to microsatellite stable CRCs. Here we review the current state of knowledge on pathways of precursor progression to CRC in LS and how these might tie in with the new findings...
July 20, 2018: Journal of Pathology
Vivian Lac, David G Huntsman
Endometriosis is a common gynecologic disease characterized by the ectopic growth of endometrial-like tissue. Despite the widespread prevalence of endometriosis, its pathogenesis remains poorly understood. A recent study by Noë et al. provides evidence that the epithelium and stroma within the same endometriotic lesions follow distinct and independent developmental trajectories. They used droplet digital PCR analysis of laser-captured epithelial-enriched and stromal-enriched endometriosis tissue and found that all 19 somatic passenger mutations analyzed were enriched exclusively in the epithelial compartment...
July 17, 2018: Journal of Pathology
Edmund Cp Chedgy, Gillian Vandekerkhove, Cameron Herberts, Matti Annala, Adam J Donoghue, Michael Sigouros, Elie Ritch, Werner Struss, Saki Konomura, Janet Liew, Sunil Parimi, Joanna Vergidis, Antonio Hurtado-Coll, Andrea Sboner, Ladan Fazli, Himisha Beltran, Kim N Chi, Alexander W Wyatt
Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similarly to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy, but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood, due to the scarcity of tumor tissue and the short life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017...
July 17, 2018: Journal of Pathology
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