Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs

Liou, Geou-Yarh; Döppler, Heike; Necela, Brian M.; Krishna, Murli; Crawford, Howard C.; Raimondo, Massimo; Störz, Peter

doi:10.1083/jcb.201301001

Cited by 238 publications

(316 citation statements)

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“…It has a very high mortality rate and is worldwide the eighth and ninth leading cause of death from cancer in men and women, respectively [106], with a 5- progress to pancreatic ductal adenocarcinoma [110]. Especially M1 macrophages appear to be attracted to Kras G12D transformed acinar cells through soluble ICAM-1, and depletion of these macrophages diminishes oncogenesis [111].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Lahmar

Keirsse

Laoui

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

108

117

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Section: Accepted Manuscriptmentioning

confidence: 99%

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Lahmar

Keirsse

Laoui

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

108

117

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“…15 In the pancreas, NF-κB signalling has been shown to play a key role in the molecular reprogramming process that underlies pancreatic acinar-to-ductal metaplasia. 16 Therefore, the putative, unique protective effect of aspirin against the development of Barrett's metaplasia might be attributable to aspirin's inhibitory effect on NF-κB that is not shared by other NSAIDs.…”

Section: Significance Of This Studymentioning

confidence: 99%

Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus

Huo

Zhang

et al. 2017

Gut

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Objective In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (NES-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced CDX2 expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of NF-κB signaling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression, and effects of aspirin on that CDX2 expression. Design We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. Results In both NES-B and NES-G cells, acid and bile salts activated NADPH oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation, and CDX2 expression induced by acid and bile salts in NES-B cells. Conclusions Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some GORD patients develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.

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“…Pancreatic acinar cells can dedifferentiate or transdifferentiate to an embryonic progenitor phenotype that expresses ductal markers, in a process termed acinar-to-ductal metaplasia (ADM) 3 . Multiple factors have been implicated in mediating ADM, including KRAS hyperactivity and increased inflammatory signalling 4–7 (FIG. 1).…”

mentioning

confidence: 99%

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

Störz

2017

Nat Rev Gastroenterol Hepatol

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256

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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. Here, the critical determinants of acinar cell plasticity are discussed, in addition to the intracellular and extracellular signalling events that drive acinar cell metaplasia and their contribution to development of PDAC.

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Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs

Abstract: Macrophages infiltrating the pancreas in response to inflammation induce cellular transdifferentiation by secreting cytokines that activate NF-κB signaling and matrix metalloproteinase expression.

Cited by 238 publications

References 45 publications

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

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