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Acinar ductal metaplasia

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https://www.readbyqxmd.com/read/29719936/induced-ptf1a-expression-in-pancreatic-ductal-adenocarcinoma-cellsactivates-acinar-gene-networks-reduces-tumorigenic-properties-and-sensitizes-cells-to-gemcitabine-treatment
#1
Brad L Jakubison, Patrick G Schweickert, Sarah E Moser, Yi Yang, Hongyu Gao, Kathleen Scully, Pamela Itkin-Ansari, Yunlong Liu, Stephen F Konieczny
Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults acinar cells undergo a dedifferentiation process termed acinar-ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix-loop-helix (bHLH) factors MIST1 and PTF1a coordinate an acinar-specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process...
May 2, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29532564/etv5-regulates-ductal-morphogenesis-with-sox9-and-is-critical-for-regeneration-from-pancreatitis
#2
Koushik K Das, Steffen Heeg, Jason R Pitarresi, Maximilian Reichert, Basil Bakir, Shigetsugu Takano, Janel L Kopp, Anja Wahl-Feuerstein, Philip Hicks, Maike Sander, Anil K Rustgi
BACKGROUND: The plasticity of pancreatic acinar cells to undergo acinar to ductal metaplasia (ADM) has been demonstrated to contribute to the regeneration of the pancreas in response to injury. Sox9 is critical for ductal cell fate and important in the formation of ADM, most likely in concert with a complex hierarchy of, as yet, not fully elucidated transcription factors. RESULTS: By using a mouse model of acute pancreatitis and three dimensional organoid culture of primary pancreatic ductal cells, we herein characterize the Ets-transcription factor Etv5 as a pivotal regulator of ductal cell identity and ADM that acts upstream of Sox9 and is essential for Sox9 expression in ADM...
March 13, 2018: Developmental Dynamics: An Official Publication of the American Association of Anatomists
https://www.readbyqxmd.com/read/29526803/pancreatic-dclk1-cells-originate-distinctly-from-pdx1-progenitors-and-contribute-to-the-initiation-of-intraductal-papillary-mucinous-neoplasm-in-mice
#3
Wanglong Qiu, Helen E Remotti, Sophia M Tang, Elizabeth Wang, Lily Dobberteen, Ayman Lee Youssof, Joo Hee Lee, Edwin C Cheung, Gloria H Su
PanINs and IPMNs are the two most common precursor lesions that can progress to invasive pancreatic ductal adenocarcinoma (PDA). DCLK1 has been identified as a biomarker of progenitor cells in PDA progressed from PanINs. To explore the potential role of DCLK1-expressing cells in the genesis of IPMNs, we compared the incidence of DCLK1-positive cells in pancreatic tissue samples from genetically-engineered mouse models (GEMMs) for IPMNs, PanINs, and acinar to ductal metaplasia by immunohistochemistry and immunofluorescence...
June 1, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29367759/genetic-and-pharmacologic-abrogation-of-snail1-inhibits-acinar-to-ductal-metaplasia-in-precursor-lesions-of-pancreatic-ductal-adenocarcinoma-and-pancreatic-injury
#4
Volker Fendrich, Frederike Jendryschek, Saskia Beeck, Max Albers, Matthias Lauth, Farzad Esni, Kristin Heeger, Janina Dengler, Emily P Slater, Julia P N Holler, Aninja Baier, Detlef K Bartsch, Jens Waldmann
Pancreatic cancer (PDAC) is one of the most dismal of human malignancies. Inhibiting or delaying the progression of precursor lesions of PDAC, pancreatic intraepthial neoplasia (PanINs), to invasive cancer, would be a major step. In the present study, we used a transgenic murine model of pancreatic cancer to evaluate the impact of a conditional knockout of the transcription factor Snail1, a major factor in epithelial-to-mesenchymal transition, on acinar-to-ductal formation and on PanIN progression. By interbreeding conditional LsL-Snailfloxf/wt ; LsL-KrasG12D and Pdx1-Cre strains, we obtained LsL-KrasG12D ;Pdx1-Cre(KP) mice, Snail1 heterozygous knockout LsL-KrasG12D ; LsL-Snailflox/- ;Pdx1-Cre(KPShet ) mice or Snail1 homozygous knockout LsL-KrasG12D ;LsL-Snailflox/flox ;Pdx1-Cre(KPS) mice...
January 25, 2018: Oncogene
https://www.readbyqxmd.com/read/29363536/cell-of-origin-affects-tumour-development-and-phenotype-in-pancreatic-ductal-adenocarcinoma
#5
Alex Y L Lee, Claire L Dubois, Karnjit Sarai, Soheila Zarei, David F Schaeffer, Maike Sander, Janel L Kopp
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour thought to arise from ductal cells via pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Modelling of different genetic events in mice suggests both ductal and acinar cells can give rise to PDAC. However, the impact of cellular context alone on tumour development and phenotype is unknown. DESIGN: We examined the contribution of cellular origin to PDAC development by inducing PDAC-associated mutations, KrasG12D expression and Trp53 loss, specifically in ductal cells ( Sox9CreER;KrasLSL-G12D ;Trp53flox/flox (' Duct:KPcKO ')) or acinar cells ( Ptf1aCreER ;KrasLSL-G12D ;Trp53flox/flox (' Acinar:KPcKO ')) in mice...
January 23, 2018: Gut
https://www.readbyqxmd.com/read/29286098/luteolin-inhibits-pancreatitis%C3%A2-induced-acinar%C3%A2-ductal-metaplasia-proliferation-and-epithelial%C3%A2-mesenchymal-transition-of-acinar-cells
#6
Xince Huang, Pravin Avinash Bhugul, Gang Fan, Tingting Ye, Shihao Huang, Shengjie Dai, Bicheng Chen, Mengtao Zhou
Luteolin, a flavone, has been demonstrated to have anti‑cancer properties. In the current study, the effects of luteolin on certain carcinogenesis‑associated changes induced by pancreatitis, which are significant risk factors for pancreatic cancer, were investigated. Male six‑week‑old C57BL6 mice used in the current study were divided into three groups; the control group, acute pancreatitis group and luteolin group. Intra‑peritoneal injection of cearulein was performed in the acute pancreatitis group and luteolin group to induce acute pancreatitis whereas the luteolin group received intra‑peritoneal injection of luteolin...
March 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29248441/kr%C3%A3-ppel-like-factor-5-increased-in-pancreatic-ductal-adenocarcinoma-promotes-proliferation-acinar-to-ductal-metaplasia-pancreatic-intraepithelial-neoplasia-and-tumor-growth-in-mice
#7
Ping He, Jong Won Yang, Vincent W Yang, Agnieszka B Bialkowska
BACKGROUND & AIMS: Activating mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs...
December 15, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29209644/new-role-of-endoplasmic-reticulum-chaperones-in-regulating-metaplasia-during-tumorigenesis
#8
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
#9
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...
August 2018: 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
#10
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...
February 15, 2018: 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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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