scholarly journals Macrophages in pancreatic cancer: Starting things off on the wrong track

2013 ◽  
Vol 202 (3) ◽  
pp. 403-405
Author(s):  
Xavier Deschênes-Simard ◽  
Yusuke Mizukami ◽  
Nabeel Bardeesy
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Inflammation ◽  
Acinar Cells ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Nuclear Factor ◽  
Oncogenic Transformation ◽  
Transcriptional Program ◽  
Cell Biol ◽  
Inflammatory Macrophages

Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor κB transcriptional program in normal pancreatic acinar cells, resulting in acinar–ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation.

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

2013 ◽  
Vol 202 (3) ◽  
pp. 563-577 ◽  
Author(s):  
Geou-Yarh Liou ◽  
Heike Döppler ◽  
Brian Necela ◽  
Murli Krishna ◽  
Howard C. Crawford ◽  
...  
Keyword(s):  
Target Genes ◽  
Acinar Cells ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Nuclear Factor ◽  
Signaling Mechanisms ◽  
Acinar To Ductal Metaplasia ◽  
Factor Α ◽  
Necrosis Factor

In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.

scholarly journals A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Evangelina López de Maturana ◽  
◽  
Juan Antonio Rodríguez ◽  
Lola Alonso ◽  
Oscar Lao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Functional Analysis ◽  
Genetic Susceptibility ◽  
In Silico ◽  
Complex Disease ◽  
Meta Analysis ◽  
Low Frequency ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Phenotypic Variance

Abstract Background Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

CCK independently activates intracellular trypsinogen and NF-κB in rat pancreatic acinar cells

2001 ◽  
Vol 280 (3) ◽  
pp. C465-C472 ◽  
Author(s):  
Bing Han ◽  
Baoan Ji ◽  
Craig D. Logsdon
Keyword(s):  
Chinese Hamster ◽  
Acinar Cells ◽  
Nuclear Factor Κb ◽  
Pancreatic Acinar Cells ◽  
Pyrrolidine Dithiocarbamate ◽  
Trypsinogen Activation ◽  
Independent Events ◽  
Dna Binding Assay ◽  
The Relationship ◽  
Stimulation Of

In the cholecystokinin (CCK) hyperstimulation model of acute pancreatitis, two early intracellular events, activation of trypsinogen and activation of nuclear factor-κB (NF-κB), are thought to be important in the development of the disease. In this study, the relationship between these two events was investigated. NF-κB activity was monitored by using a DNA binding assay and mob-1 chemokine gene expression. Intracellular trypsin activity was measured by using a fluorogenic substrate. Protease inhibitors including FUT-175, Pefabloc, and E-64d prevented CCK stimulation of intracellular trypsinogen and NF-κB activation. Likewise, the NF-κB inhibitors pyrrolidine dithiocarbamate and N-acetyl-l-cysteine inhibited CCK stimulation of NF-κB and intracellular trypsinogen activation. These results suggested a possible codependency of these two events. However, CCK stimulated NF-κB activation in Chinese hamster ovary-CCKAcells, which do not express trypsinogen, indicating that trypsin is not necessary for CCK activation of NF-κB. Furthermore, adenovirus-mediated expression in acinar cells of active p65 subunits to stimulate NF-κB, or of inhibitory κB-α molecules to inhibit NF-κB, did not affect either basal or CCK-mediated trypsinogen activation. Thus trypsinogen and NF-κB activation are independent events stimulated by CCK.

Abstract PO-056: Insulin receptor signaling in pancreatic acinar cells contributes to pancreatic cancer development

2021 ◽  
Author(s):  
Anni M. Y. Zhang ◽  
Jenny C. C. Yang ◽  
Twan J. J. de Winter ◽  
David F. Schaeffer ◽  
Janel L. Kopp ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Acinar Cells ◽  
Cancer Development ◽  
Pancreatic Acinar Cells ◽  
Receptor Signaling ◽  
Insulin Receptor Signaling

scholarly journals Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2606
Author(s):  
Carlotta Paoli ◽  
Alessandro Carrer
Keyword(s):  
Pancreatic Cancer ◽  
Ex Vivo ◽  
Acinar Cells ◽  
Lineage Tracing ◽  
Metabolic Reprogramming ◽  
Pancreatic Acinar Cells ◽  
Ductal Adenocarcinoma ◽  
Molecular Features ◽  
The Impact

The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.

scholarly journals Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer

2018 ◽  
Vol 115 (18) ◽  
pp. 4767-4772 ◽  
Author(s):  
Koji Tamura ◽  
Jun Yu ◽  
Tatsuo Hata ◽  
Masaya Suenaga ◽  
Koji Shindo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Er Stress ◽  
Odds Ratio ◽  
Cancer Susceptibility ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Familial Pancreatic Cancer ◽  
Coding Regions ◽  
Familial Cases ◽  
Genes Encoding

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15–76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.

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