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Pancreatitis
Regulation of the Pancreatic Exocrine Differentiation Program and Morphogenesis by Onecut 1/Hnf6
The Onecut 1 transcription factor (Oc1, a.k.a. HNF6) promotes differentiation of endocrine and duct cells of the pancreas; however, it has no known role in acinar cell differentiation. We sought to better understand the role of Oc1 in exocrine pancreas development and to identify its direct transcriptional targets.The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for >30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler ɑ-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS’s ability to promote PDAC.Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model
Heavy alcohol drinking is associated with pancreatitis, whereas moderate intake lowers the risk. Mice fed ethanol long term show no pancreas damage unless adaptive/protective responses mediating proteostasis are disrupted. Pancreatic acini synthesize digestive enzymes (largely serine hydrolases) in the endoplasmic reticulum (ER), where perturbations (eg, alcohol consumption) activate adaptive unfolded protein responses orchestrated by spliced X-box binding protein 1 (XBP1). Here, we examined ethanol-induced early structural changes in pancreatic ER proteins.Cholecystokinin Receptor-Targeted Polyplex Nanoparticle Inhibits Growth and Metastasis of Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) remains the most aggressive malignancy with the lowest 5-year survival rate of all cancers in part owing to the lack of tumor-specific therapy and the rapid metastatic nature of this cancer. The gastrointestinal peptide gastrin is a trophic peptide that stimulates growth of PDAC in an autocrine fashion by interaction with the cholecystokinin receptor that is overexpressed in this malignancy.E47 Governs the MYC-CDKN1B/p27KIP1-RB Network to Growth Arrest PDA Cells Independent of CDKN2A/p16INK4A and Wild-Type p53
Oncogenic mutations in KRAS, coupled with inactivation of p53, CDKN2A/p16INK4A, and SMAD4, drive progression of pancreatic ductal adenocarcinoma (PDA). Overexpression of MYC and deregulation of retinoblastoma (RB) further promote cell proliferation and make identifying a means to therapeutically alter cell-cycle control pathways in PDA a significant challenge. We previously showed that the basic helix-loop-helix transcription factor E47 induced stable growth arrest in PDA cells in vitro and in vivo.Increased Pancreatic Protease Activity in Response to Antibiotics Impairs Gut Barrier and Triggers Colitis
Antibiotic (ABx) therapy is associated with increased risk for Crohn’s disease but underlying mechanisms are unknown. We observed high fecal serine protease activity (PA) to be a frequent side effect of ABx therapy. The aim of the present study was to unravel whether this rise in large intestinal PA may promote colitis development via detrimental effects on the large intestinal barrier.Mind the Gap: Crossing Boundaries to Establish Reparative Metaplasia
In this issue of Cellular and Molecular Gastroenterology and Hepatology, Agoston et al1 report that, in an esophago-jejuno anastomosed rat model, metaplastic columnar-lined esophagus develops within a wound-healing process in the distal edge of a region of ulceration, starting distally at the esophago-jejuno anastomosis. This ulcer migrated proximally, and the length of the columnar-lined esophagus elongated in the time course after the anastomotic surgery. They also concluded that the columnar-lined esophagus was caused through migration of jejunal cells into the esophagus, as the immunoprofile of columnar-lined esophagus was similar to jejunal crypt epithelium.Pancreas 3D Organoids: Current and Future Aspects as a Research Platform for Personalized Medicine in Pancreatic Cancer
Pancreatic ductal adenocarcinoma is one of the most aggressive forms of cancer, and the third leading cause of cancer-related mortality in the United States. Although important advances have been made in the last decade, the mortality rate of pancreatic ductal adenocarcinoma has not changed appreciably. This review summarizes a rapidly emerging model of pancreatic cancer research, focusing on 3-dimensional organoids as a powerful tool for several applications, but above all, representing a step toward personalized medicine.Pancreatic HIF2α Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm
Tissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2α. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2α expression in the pancreas have remained undefined.Location, Location, Location . . . It Is Important in Pancreatitis, Too
The phrase “location, location, location” has been used in the real estate business for more than 90 years to convey the overriding importance of location in determining value, function, and opportunity. It now may be important in how we approach pancreatitis.Mitogen-activated Protein Kinase Kinase Activity Maintains Acinar-to-Ductal Metaplasia and Is Required for Organ Regeneration in Pancreatitis
Mitogen-activated protein kinase (MAPK) signaling in the exocrine pancreas has been extensively studied in the context of pancreatic cancer, where its potential as a therapeutic target is limited by acquired drug resistance. However, its role in pancreatitis is less understood. We investigated the role of mitogen-activated protein kinase kinase (MEK)-initiated MAPK signaling in pancreatitis to determine the potential for MEK inhibition in treating pancreatitis patients.Targeted Inhibition of Pancreatic Acinar Cell Calcineurin Is a Novel Strategy to Prevent Post-ERCP Pancreatitis
There is a pressing need to develop effective preventative therapies for post–endoscopic retrograde cholangiopancreatography pancreatitis (PEP). We showed that early PEP events are induced through the calcium-activated phosphatase calcineurin and that global calcineurin deletion abolishes PEP in mice. A crucial question is whether acinar cell calcineurin controls the initiation of PEP in vivo.Necrosis, Apoptosis, Necroptosis, Pyroptosis: It Matters How Acinar Cells Die During Pancreatitis
Acute pancreatitis is an unpredictable disease. Most patients develop edema of the pancreas and quickly recover whatever the therapy (or lack thereof), but a minority develop severe complications with significant morbidity and mortality. When the disease is studied in experimental animal models,1 to distinguish between the 2 forms, it appears that all processes begin in acinar cells2 but then develop in different directions. The way acinar cells undergo injury and cell death seems to determine the ultimate severity.Targeting αv Integrins in Pancreatic Fibrosis: Progress in Resolving the Scar
Integrins are the glue that maintain cell-to-cell adhesion and are found in nearly all cell types and function as heterodimeric cell surface receptors. Although not regarded as active signaling receptors in the basal state, integrins transduce signals that regulate fibrosis, angiogenesis, cellular migration, and other wound-healing processes during pathologic conditions.1,2 In this issue of Cellular and Molecular Gastroenterology and Hepatology, Ulmasov et al3 report that a synthetic peptide (CWHM-12) containing a conserved Arg-Gly-Asp (RGD) integrin-recognition domain ameliorated cerulein-induced pancreatic fibrosis and pancreatic stellate cell (PSC) activation by inhibiting transforming growth factor (TGF)-β activation.Inhibitors of Arg-Gly-Asp-Binding Integrins Reduce Development of Pancreatic Fibrosis in Mice
Pancreatic stellate cells (PSCs) regulate the development of chronic pancreatitis (CP) and are activated by the cytokine transforming growth factor β (TGFB). Integrins of the αv family promote TGFB signaling in mice, probably by interacting with the Arg-Gly-Asp (RGD) sequence of the TGFB latency-associated peptide, which frees TGFB to bind its cellular receptors. However, little is known about the role of integrins in the development of CP. We investigated the effects of small-molecule integrin inhibitors in a mouse model of CP.Lysosome-Associated Membrane Protein-2: A Major Player in the Pathogenesis of Chronic Pancreatitis
The mechanisms involved in the development of either acute or chronic pancreatitis are not well understood, but previous reports have suggested that the pathogenesis of acute pancreatitis may involve a blockade of autophagic flux.1 In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Mareninova et al2 from the Gukovskaya and Lerch groups have reported the results of studies investigating the role of lysosome-associated membrane protein-2 (LAMP-2) in the development of acute and chronic pancreatitis and in the regulation of successful autophagy in pancreatic acinar cells.Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation of Hhex in Mice
Perturbations in pancreatic ductal bicarbonate secretion cause chronic pancreatitis. The physiologic mechanism of ductal secretion is known, but its transcriptional control is not. We determine the role of the transcription factor hematopoietically expressed homeobox protein (Hhex) in ductal secretion and pancreatitis.Induction of Autophagy: A Novel Anti-inflammatory Function of High-Density Lipoprotein
The inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and the risk for development of atherosclerotic cardiovascular disease has led to extensive studies of HDL and its major apoprotein apolipoprotein A-I (apoA-I) with respect to their antiatherogenic role. The ability of HDL and apoA-I to promote the efflux of cholesterol from cells in peripheral tissues, including macrophages in atherosclerotic plaques, and to transport the cholesterol to the liver for excretion via biliary secretion is considered their major atheroprotective role.Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice
In the pancreas, activation of primary sensory nerves through the transient receptor potential vanilloid-1 (TRPV1) ion channel contributes to the early stages of development of pancreatitis. Little is known about the mechanism by which this occurs. We investigated whether leukotriene B4 (LTB4) is an endogenous agonist of TRPV1 and mediates pancreatitis.
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