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Acinar to ductal metaplasia

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https://www.readbyqxmd.com/read/29209644/new-role-of-endoplasmic-reticulum-chaperones-in-regulating-metaplasia-during-tumorigenesis
#1
Jieli Shen, Daisy F Rangel, Dat Ha, Amy S Lee
Metaplasia is emerging as a key process in tumorigenesis. We discovered that 2 essential endoplasmic reticulum (ER) chaperones, 78-kilodalton glucose-regulated protein (GRP78) and 94-kilodalton glucose-regulated protein (GRP94) have a role in metaplasia. Grp78 haploinsufficiency in the mouse pancreas impairs acinar-to-ductal metaplasia, whereas in the uterus, Grp94 loss induces squamous cell metaplasia; both resulting in tumor suppression.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29155449/baicalein-inhibits-acinar-to-ductal-metaplasia-of-pancreatic-acinal-cell-ar42j-via-improving-the-inflammatory-microenvironment
#2
Wei-Ling Pu, Ying-Ying Luo, Ru-Yu Bai, Ao-Wei Guo, Kun Zhou, Yun-Sha Zhang, Lin Miao, Curzio Rüegg, Micheal O Hottiger, Xiu-Mei Gao, Li-Kang Sun
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers. Recent research has demonstrated that chronic pancreatitis (CP) is associated with an increased risk of PDAC, partly due to acinar-to-ductal metaplasia (ADM). Baicalein has been shown to exert anti-inflammatory and anti-tumor effects for CP or PDAC, respectively. The aim of our study was to investigate the effect of baicalein, and the putative underlying mechanism, on inflammatory cytokines-induced ADM of rat pancreatic acinar cell line AR42J...
November 20, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29059173/sox9-activity-is-induced-by-oncogenic-kras-to-affect-mdc1-and-mcms-expression-in-pancreatic-cancer
#3
H Zhou, Y Qin, S Ji, J Ling, J Fu, Z Zhuang, X Fan, L Song, X Yu, P J Chiao
SRY (sex determining region Y)-box 9 (SOX9) is required for oncogenic Kras-mediated acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasias (PanINs) and ultimately pancreatic ductal adenocarcinoma (PDAC). However, how oncogenic Kras affects SOX9 activity is not yet understood, and SOX9-associated genes in PDAC are also unknown at all. Here, we investigated the mechanistic link between SOX9 and oncogenic Kras, studied biological function of SOX9, and identified SOX9-related genes and their clinical significance in patients with PDAC...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/28902792/paracrine-secretion-of-transforming-growth-factor-%C3%AE-by-ductal-cells-promotes-acinar-to-ductal-metaplasia-in-cultured-human-exocrine-pancreas-tissues
#4
Naoki Akanuma, Jun Liu, Geou-Yarh Liou, Xue Yin, Kaitlyn R Bejar, Chengyang Liu, Lu-Zhe Sun, Peter Storz, Pei Wang
OBJECTIVE: We aimed to evaluate the contribution of acinar-to-ductal metaplasia (ADM) to the accumulation of cells with a ductal phenotype in cultured human exocrine pancreatic tissues and reveal the underlying mechanism. METHODS: We sorted and cultured viable cell populations in human exocrine pancreatic tissues with a flow cytometry-based lineage tracing method to evaluate possible mechanisms of ADM. Cell surface markers, gene expression pattern, and sphere formation assay were used to examine ADM...
October 2017: Pancreas
https://www.readbyqxmd.com/read/28860646/metaplasia-tissue-injury-adaptation-and-a-precursor-to-the-dysplasia-cancer-sequence
#5
REVIEW
Veronique Giroux, Anil K Rustgi
Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar-ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia...
October 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28832971/class-i-histone-deacetylase-inhibition-improves-pancreatitis-outcome-by-limiting-leukocyte-recruitment-and-acinar-to-ductal-metaplasia
#6
Marta Bombardo, Enrica Saponara, Ermanno Malagola, Rong Chen, Gitta M Seleznik, Cecile Haumaitre, Evans Quilichini, Anja Zabel, Theresia Reding, Rolf Graf, Sabrina Sonda
BACKGROUND AND PURPOSE: Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. EXPERIMENTAL APPROACH: We analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models...
November 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28774888/development-of-autoimmune-pancreatitis-is-independent-of-cdkn1a-p21-mediated-pancreatic-inflammation
#7
Gitta M Seleznik, Theresia Reding, Lukas Peter, Anurag Gupta, Sabrina G Steiner, Sabrina Sonda, Caroline S Verbeke, Emmanuel Dejardin, Igor Khatkov, Stephan Segerer, Mathias Heikenwalder, Rolf Graf
OBJECTIVE: Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development...
August 3, 2017: Gut
https://www.readbyqxmd.com/read/28752115/acinar-to-ductal-metaplasia-induced-by-transforming-growth-factor-beta-facilitates-kras-g12d-driven-pancreatic-tumorigenesis
#8
Nicolas Chuvin, David F Vincent, Roxane M Pommier, Lindsay B Alcaraz, Johann Gout, Cassandre Caligaris, Karam Yacoub, Victoire Cardot, Elodie Roger, Bastien Kaniewski, Sylvie Martel, Celia Cintas, Sophie Goddard-Léon, Amélie Colombe, Julie Valantin, Nicolas Gadot, Emilie Servoz, Jennifer Morton, Isabelle Goddard, Anne Couvelard, Vinciane Rebours, Julie Guillermet, Owen J Sansom, Isabelle Treilleux, Ulrich Valcourt, Stéphanie Sentis, Pierre Dubus, Laurent Bartholin
BACKGROUND & AIMS: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive...
September 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28738823/metformin-suppresses-cancer-initiation-and-progression-in-genetic-mouse-models-of-pancreatic-cancer
#9
Ke Chen, Weikun Qian, Zhengdong Jiang, Liang Cheng, Jie Li, Liankang Sun, Cancan Zhou, Luping Gao, Meng Lei, Bin Yan, Junyu Cao, Wanxing Duan, Qingyong Ma
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer...
July 24, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28701342/activating-transcription-factor-3-promotes-loss-of-the-acinar-cell-phenotype-in-response-to-cerulein-induced-pancreatitis-in-mice
#10
Elena N Fazio, Claire C Young, Jelena Toma, Michael Levy, Kurt R Berger, Charis L Johnson, Rashid Mehmood, Patrick Swan, Alphonse Chu, Sean P Cregan, F Jeffrey Dilworth, Christopher J Howlett, Christopher L Pin
Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis...
September 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28639695/glycogen-synthase-kinase-3%C3%AE-ablation-limits-pancreatitis-induced-acinar-to-ductal-metaplasia
#11
Li Ding, Geou-Yarh Liou, Daniel M Schmitt, Peter Storz, Jin-San Zhang, Daniel D Billadeau
Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models...
September 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28593186/origin-of-barrett-s-epithelium-esophageal-submucosal-glands
#12
Katherine S Garman
The origin of the progenitor cell for Barrett's esophagus remains a major unsolved mystery. Understanding the source of this progenitor may improve strategies to prevent the development of esophageal adenocarcinoma. Esophageal submucosal glands (ESMGs) and ducts may serve as a potential source of progenitor cells that respond to esophageal injury. Through the use of human histologic and molecular analysis, ESMGs and ducts have been described in physical continuity with areas of columnar esophagus, and shared mutations have been described between ESMG ducts and Barrett's esophagus...
July 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28572084/ductular-and-proliferative-response-of-esophageal-submucosal-glands-in-a-porcine-model-of-esophageal-injury-and-repair
#13
Leandi Krüger, Liara M Gonzalez, Tiffany A Pridgen, Shannon J McCall, Richard J von Furstenberg, Ivan Harnden, Gwendolyn E Carnighan, Abigail M Cox, Anthony T Blikslager, Katherine S Garman
Esophageal injury is a risk factor for diseases such as Barrett's esophagus (BE) and esophageal adenocarcinoma. To improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in the human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer. In addition, the SOX9 transcription factor has been associated with generation of columnar epithelium and the pathogenesis of BE and is present in ESMGs...
September 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28542719/ibuprofen-and-diclofenac-treatments-reduce-proliferation-of-pancreatic-acinar-cells-upon-inflammatory-injury-and-mitogenic-stimulation
#14
Marta Bombardo, Ermanno Malagola, Rong Chen, Alina Rudnicka, Rolf Graf, Sabrina Sonda
BACKGROUND AND PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered to manage the pain typically found in patients suffering from pancreatitis. NSAIDs also display anti-proliferative activity against cancer cells; however, their effects on normal, untransformed cells are poorly understood. Here, we evaluated whether NSAIDs inhibit the proliferation of pancreatic acinar cells during the development of acute pancreatitis. EXPERIMENTAL APPROACH: The NSAIDs ibuprofen and diclofenac were administered to C57BL/6 mice after induction of pancreatitis with serial injections of cerulein...
May 19, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28514653/the-presence-of-interleukin-13-at-pancreatic-adm-panin-lesions-alters-macrophage-populations-and-mediates-pancreatic-tumorigenesis
#15
Geou-Yarh Liou, Ligia Bastea, Alicia Fleming, Heike Döppler, Brandy H Edenfield, David W Dawson, Lizhi Zhang, Nabeel Bardeesy, Peter Storz
The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28461470/grp78-haploinsufficiency-suppresses-acinar-to-ductal-metaplasia-signaling-and-mutant-kras-driven-pancreatic-tumorigenesis-in-mice
#16
Jieli Shen, Dat P Ha, Genyuan Zhu, Daisy F Rangel, Agnieszka Kobielak, Parkash S Gill, Susan Groshen, Louis Dubeau, Amy S Lee
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras(G12D/+);p53(f/+) (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28368927/heterotopic-pancreas-of-the-gastrointestinal-tract-and-associated-precursor-and-cancerous-lesions-systematic-pathologic-studies-of-165-cases
#17
Sun-Young Jun, Dahye Son, Mi-Ju Kim, Sung Joo Kim, Soyeon An, Young Soo Park, Sook Ryun Park, Kee Don Choi, Hwoon-Yong Jung, Song Cheol Kim, Jeong Hwan Yook, Byung-Sik Kim, Seung-Mo Hong
Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs (57 gastric [35%], 56 duodenal [34%], 30 omental [18%], and 22 jejunal [13%]). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P<0.001), and more frequently associated with lymphoid cuffs (P=0.03) than incidentally found HPs. Gastric/jejunal HPs were more frequently symptomatic (P<0...
June 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28270694/acinar-cell-plasticity-and-development-of-pancreatic-ductal-adenocarcinoma
#18
REVIEW
Peter Storz
Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention...
May 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28162998/common-telomere-changes-during-in%C3%A2-vivo-reprogramming-and-early-stages-of-tumorigenesis
#19
Rosa M Marión, Isabel López de Silanes, Lluc Mosteiro, Benjamin Gamache, María Abad, Carmen Guerra, Diego Megías, Manuel Serrano, Maria A Blasco
Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length...
February 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28099259/smad2-3-linker-phosphorylation-is-a-possible-marker-of-pancreatic-stem-progenitor-cells-in-the-regenerative-phase-of-acute-pancreatitis
#20
Masayuki Sakao, Yutaku Sakaguchi, Ryo Suzuki, Yu Takahashi, Masanobu Kishimoto, Toshiro Fukui, Kazushige Uchida, Akiyoshi Nishio, Koichi Matsuzaki, Kazuichi Okazaki
OBJECTIVES: The aims of this study are to characterize cell proliferation and differentiation during regeneration after pancreatitis and pancreatic buds during development to evaluate the role of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr) in positive cells. METHODS: Male C57BL/6 mice received hourly intraperitoneal injections of cerulein and were analyzed after induced pancreatitis. Pancreatitis-affected tissue sections and pancreatic buds were immunostained for pSmad2/3L-Thr, with other markers thought to be stem/progenitor markers of the pancreas...
May 2017: Pancreas
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