Extracellular Cleavage of E-Cadherin by Leukocyte Elastase During Acute Experimental Pancreatitis in Rats

Mayerle, Julia; Schnekenburger, Jürgen; Krüger, Burkhard; Kellermann, Josef; Ruthenbürger, Manuel; Weiss, Frank Ulrich; Nalli, Angel; Domschke, Wolfram; Lerch, Markus M.

doi:10.1053/j.gastro.2005.08.002

Cited by 115 publications

(108 citation statements)

References 55 publications

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“…The target for elastase is the adhesion molecule E-cadherin, which is expressed by the tumor cells and known to mediate cell-cell contact. We could demonstrate that neutrophil elastase cleaved surface E-cadherin of PDAC tumor cells, extending previously published data by others for an acute pancreatitis model [20].Of note, PFA-fixed PMNs also caused dyshesion of the tumor cell layer, and the surface-bound PMN elastase was able to cleave E-cadherin. These data are in line with the fact that cell-surface-associated elastase retained its enzymatic activity.…”

supporting

confidence: 89%

Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase‐mediated degradation of E‐cadherin in pancreatic tumors

et al. 2012

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Pancreatic ductal adenocarcinoma (PDAC) presenting with a micropapillary growth pattern is frequently associated with a prominent neutrophil infiltration into the tumor. The relevance of neutrophil infiltrates for tumor progression, however, is still debated. To gain insight into the role of polymorphonuclear neutrophils (PMNs) in PDAC, we assessed their effect on pancreatic tumor cells grown in vitro as monolayers. Time-lapse video microscopy showed a PMN-induced dyshesion of the tumor cells, and subsequent experiments revealed that this dyshesion was due to PMN elastase-mediated degradation of E-cadherin, an adhesion molecule that mediates the intercellular contact of the tumor cells. E-cadherin degradation by elastase or -(for comparison) down-modulation by specific siRNA, significantly increased the migratory capacity of the pancreatic tumor cells, leading to the hypothesis that PMNs could contribute to the invasive tumor growth. To address this issue, biopsies of patients with PDAC (n = 112) were analyzed. We found that E-cadherin expression correlated negatively with PMN infiltration, compatible with the notion that E-cadherin is cleaved by PMN-derived elastase, which in turn could result in the dispersal of the tumor cells, enhanced migratory capacity and thus invasive tumor growth.Keywords: E-cadherin r Invasion r Pancreatic cancer r PMN elastase r Polymorphonuclear neutrophils Supporting Information available online IntroductionPancreatic ductal adenocarcinoma (PDAC) is the fourth most common cancer-related death in Western countries with a devasCorrespondence: Prof. Gertrud M. Hänsch e-mail: Maria.Haensch@urz-uni-heidelberg.de tating prognosis of an overall 5-year survival rate of less than 5% [1]. The dismal prognosis is due to the aggressive and invasive tumor growth, early metastasis, and resistance to radiation and chemotherapy [1,2]. A hallmark of pancreatic cancer is the distinct intratumoral inflammatory reaction, with an infiltration of T lymphocytes, macrophages [3][4][5]. Infiltration of polymorphonuclear neutrophils (PMNs) was described in PDAC and cancers of the periampullary region, where intratumor PMN infiltration was C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3370 Matthias M. Gaida et al. Eur. J. Immunol. 2012. 42: 3369-3380 associated with a "micropapillary" and "scattered" growth pattern, poor histological differentiation and a poor prognosis [6,7]. The role of the PMNs in the tumor progression is controversially discussed, and not yet conclusively understood [3,8,9]. PMNs have the potential to kill tumor cells, either directly [10] or by Ab-dependent cell-mediated cytotoxicity [11]. However, adverse effects of PMNs such as the promotion of aggressive tumor growth and an increased metastatic potential have been described, for example, in mammary cancer [12,13]. An attractive hypothesis is that PMN-derived matrix-degrading proteases such as the metalloproteinases (MMP) 1, MMP2, and MMP9 or the neutrophil elastase [14][15][16] Results PMN-derived elastase...

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supporting

confidence: 89%

Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase‐mediated degradation of E‐cadherin in pancreatic tumors

et al. 2012

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“…Cleavage of cadherins by proteinases, with subsequent nuclear translocation of β-catenin and activation of β-catenindependent transcriptional events, has been documented in endothelial cells (29,30), in keratinocytes (27), and during pancreatitis (31). Shedding of an extracellular fragment of E-cadherin in animal models of lung injury has been reported (32,33).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signaling

Zemans

Briones

Campbell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

170

148

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Injury to the epithelium is integral to the pathogenesis of many inflammatory lung diseases, and epithelial repair is a critical determinant of clinical outcome. However, the signaling pathways regulating such repair are incompletely understood. We used in vitro and in vivo models to define these pathways. Human neutrophils were induced to transmigrate across monolayers of human lung epithelial cells in the physiological basolateral-to-apical direction. This allowed study of the neutrophil contribution not only to the initial epithelial injury, but also to its repair, as manifested by restoration of transepithelial resistance and reepithelialization of the denuded epithelium. Microarray analysis of epithelial gene expression revealed that neutrophil transmigration activated β-catenin signaling, and this was verified by real-time PCR, nuclear translocation of β-catenin, and TOPFlash reporter activity. Leukocyte elastase, likely via cleavage of E-cadherin, was required for activation of β-catenin signaling in response to neutrophil transmigration. Knockdown of β-catenin using shRNA delayed epithelial repair. In mice treated with intratracheal LPS or keratinocyte chemokine, neutrophil emigration resulted in activation of β-catenin signaling in alveolar type II epithelial cells, as demonstrated by cyclin D1 expression and/or reporter activity in TOPGAL mice. Attenuation of β-catenin signaling by IQ-1 inhibited alveolar type II epithelial cell proliferation in response to neutrophil migration induced by intratracheal keratinocyte chemokine. We conclude that β-catenin signaling is activated in lung epithelial cells during neutrophil transmigration, likely via elastase-mediated cleavage of E-cadherin, and regulates epithelial repair. This pathway represents a potential therapeutic target to accelerate physiological recovery in inflammatory lung diseases.

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“…As to the pathophysiological mechanism by which Ecadherin is lost, recent studies demonstrated several causes for reductions in E-cadherin such as abrogating E-cadherin expression (22,23), disruption of the Ecadherin and catenin complex (24), deregulated proteases (25), exposure to chelates (26), ischemia/ATP depletion (27), and endocytosis from the intracellular junction (28,29).…”

Section: Discussionmentioning

confidence: 99%

Effects of Helicobacter pylori Infection on Gastric Parietal Cells and E-cadherin in Mongolian Gerbils

et al. 2013

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Abstract. Atrophic gastritis caused by infection withHelicobacter pylori is characterized by parietal cell loss, which is a main risk factor for gastric cancer. Parietal cells play a crucial role in the regulation of cell lineage maturation and proliferation in the gastric units. Among the classical cadherins, E-cadherin plays an important role not only in epithelial cell-cell connections, but also in the maintenance of epithelial polarity and gastric glandular architecture and regulation of cell proliferation. The aim of this study is to elucidate how parietal cells and E-cadherin are altered in gastritis with Helicobacter pylori infection. We studied the effects of Helicobacter pylori on gastric mucosal E-cadherin 2 weeks after inoculation and investigated the relationship between parietal cell loss and the amount of E-cadherin on parietal cells in Mongolian gerbils. The number of parietal cells and amount of staining of E-cadherin below the isthmus were investigated by immunohistochemistry. It was shown that a reduction in intercellular E-cadherin preceded the disappearance of parietal cells. The gastric glands where parietal cells were lost were replaced by mucus secreting cells without E-cadherin. These results suggest that Helicobacter pylori damaged E-cadherin on parietal cells and caused massive parietal cell loss, leading to the deregulation of gastric morphology.

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Extracellular Cleavage of E-Cadherin by Leukocyte Elastase During Acute Experimental Pancreatitis in Rats

Cited by 115 publications

References 55 publications

Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase‐mediated degradation of E‐cadherin in pancreatic tumors

Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase‐mediated degradation of E‐cadherin in pancreatic tumors

Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signaling

Effects of Helicobacter pylori Infection on Gastric Parietal Cells and E-cadherin in Mongolian Gerbils

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