Connective tissue growth factor production by activated pancreatic stellate cells in mouse alcoholic chronic pancreatitis

Charrier, Alyssa; Brigstock, David R.

doi:10.1038/labinvest.2010.82

Cited by 43 publications

(49 citation statements)

References 42 publications

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“…collagen) in a CCN2-dependent manner following ethanol exposure. Since we previously showed that activated PSC are the main producers of collagen and CCN2 in a mouse model of CP (Charrier and Brigstock 2010), the goal of the present study was to determine the action of miRs up-or down-stream of CCN2 during PSC activation. We initially performed a miR microarray on total pancreatic RNA collected from mice with ethanol-induced CP.…”

Section: Resultsmentioning

confidence: 99%

Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes

Charrier

Chen

et al. 2014

J. Cell Commun. Signal.

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Pancreatitis is an inflammatory condition of the pancreas which, in its chronic form, involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer, and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). In response to noxious agents such as alcohol-excessive consumption of which is a major cause of pancreatitis in the West-normally quiescent PSC undergo a phenotypic and functional transition to activated myofibroblasts which produce and deposit collagen at high levels. This process is regulated by connective tissue growth factor (CCN2), expression of which is highly up-regulated in activated PSC. We show that CCN2 production by activated PSC is associated with enhanced expression of microRNA-21 (miR-21) which was detected at high levels in activated PSC in a murine model of alcoholic chronic pancreatitis. A positive feedback loop between CCN2 and miR-21 was identified that resulted in enhancement of their respective expression as well as that of collagen α1(I). Both miR-21 and CCN2 mRNA were present in PSC-derived exosomes, which were characterized as 50-150 nm CD9-positive nanovesicles. Exosomes from CCN2-GFP-or miR-21-GFPtransfected PSC were taken up by other PSC cultures, as shown by direct fluorescence or qRT-PCR for GFP. Collectively these studies establish miR-21 and CCN2 as participants in a positive feedback loop during PSC activation and as components of the molecular payload in PSC-derived exosomes that can be delivered to other PSC. Thus interactions between cellular or exosomal miR-21 and CCN2 represent novel aspects of fibrogenic regulation in PSC. Summary Chronic injury in the pancreas is associated with fibrotic pathology which is driven in large part by CCN2-dependent collagen production in pancreatic stellate cells. This study shows that CCN2 up-regulation in PSC is associated with increased expression of miR-21 which, in turn, is able to stimulate CCN2 expression further via a positive feedback loop. Additionally miR-21 and CCN2 were identified in PSC-derived exosomes which effected their delivery to other PSC. The cellular and exosomal miR-21-CCN2 axis is a novel component in PSC fibrogenic signaling.

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Section: Resultsmentioning

confidence: 99%

Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes

Charrier

Chen

et al. 2014

J. Cell Commun. Signal.

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“…Examples are the fibroblast-growth factors -1 and -2 (FGF-1 and -2), IGF-1, connective tissue growth factor (CTGF), and EGF (7,8,10,14,23,25,39). Interestingly, the extent to which endogenous protective and injurious factors interact with each other has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Although utilization of experimental models has helped identify molecular mechanisms linked to development of CP (19,32,41,47), significant gaps persist in our knowledge of endogenous factors that function to either inhibit or amplify the inflammatory-fibrosis cascade (7,9,41), a key component of the CP disease process.…”

mentioning

confidence: 99%

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Rastellini

Han

Bhatia

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This signal increased the cell adhesion and migration of PSCs, leading to PSC activation [55]. CTGF was supplied from activated PSCs themselves, which were activated by exogenous stimulants such as ethanol [56]. Another report described that pancreatic cancer cells could also become a source of CTGF in pancreatic cancer tissue [57].…”

Section: Detailed Mechanism Of Psc Activation In Pancreatic Cancermentioning

confidence: 99%

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

2013

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Chronic inflammation has a certain impact on the carcinogenesis of the digestive organs. The characteristic tissue structure of pancreatic cancer, desmoplasia, results from inflammatory processes induced by cancer cells and stromal cells. Concerning the progression of pancreatic cancer, recent research has clarified the pivotal role of tumorstromal interaction, which promotes the development of an invasive phenotype of cancer and provides survival advantages against chemotherapeutic agents or immune surveillance. Tumor stromal cells such as pancreatic stellate cells and immune cells establish a microenvironment that protects cancer cells through complex interactions. The microenvironment of pancreatic cancer acts as a niche for pancreatic cancer stem cells from which therapy-resistance and disease recurrence develop. Inhibition of the stromal functions or restoration of the immune reaction against cancer cells has therapeutic benefits that enhance the efficacy of conventional therapies. Some of the recent advances in this field are now under evaluation in clinical settings, but many problems must be overcome to establish a radical therapy for pancreatic cancer. This review summarizes current knowledge about the tumor-promoting stromal functions, immune system modulation and therapeutic strategies targeting tumorstromal interactions in pancreatic cancer.

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Connective tissue growth factor production by activated pancreatic stellate cells in mouse alcoholic chronic pancreatitis

Cited by 43 publications

References 42 publications

Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes

Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

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