Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer

Gukovsky, Ilya; Li, Ning; Todoric, Jelena; Gukovskaya, Anna S.; Karin, Michael

doi:10.1053/j.gastro.2013.02.007

Cited by 289 publications

(269 citation statements)

References 193 publications

(70 reference statements)

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“…These data illustrate the contribution of chronic inflammation to pancreatic carcinogenesis. Although it is not fully understood how inflammation enhances PDAC carcinogenesis, several mechanisms have been proposed and reviewed (12). For example, activation of oncogenic Kras creates an inflammatory tumor microenvironment by increasing the production of inflammatory mediators, including interleukin (IL)-6, IL-11, TNF-a, and IL-1a.…”

Section: Inflammation and Pancreatic Tumorigenesismentioning

confidence: 99%

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

Yang

DiPaola

et al. 2014

Cancer Prevention Research

132

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Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFkB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/b-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer. Cancer Prev Res; 7(4); 388-97. Ó2014 AACR.

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Section: Inflammation and Pancreatic Tumorigenesismentioning

confidence: 99%

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

Yang

DiPaola

et al. 2014

Cancer Prevention Research

132

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“…Of these, pancreatitis (including its acute and chronic forms) is one of the most frequently studied diseases. Although the pathogenesis mechanisms underlying the role of pancreatitis in PC etiology are still unclear, the molecular pathway for this association had been put forward by several hypotheses (Sakorafas et al, 2012;Gukovsky et al, 2013;Pinho et al, 2014;Kolodecik et al, 2014). Just like other benign diseases are associated with an increased cancer risk in the target organs (e.g., hepatitis and liver cancer, gastritis and gastric cancer), increased cell turnover and defective DNA repair in pancreatitis cases could lead to the occurrence of PC.…”

Section: Introductionmentioning

confidence: 99%

Association Between Pancreatitis and Subsequent Risk of Pancreatic Cancer: a Systematic Review of Epidemiological Studies

Tong¹,

Geng²,

Chai³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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This study aimed to summarize published epidemiological evidence for the relationship between pancreatitis and subsequent risk of pancreatic cancer (PC). We searched Medline and Embase for epidemiological studies published by February 5 th , 2014 examining the risk of PC in pancreatitis patients using highly inclusive algorithms. Information about first author, year of publication, country of study, recruitment period, type of pancreatitis, study design, sample size, source of controls and attained age of subjects were extracted by two researchers and Stata 11.0 was used to perform the statistical analyses and examine publication bias. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the random effects model. A total of 17 articles documenting 3 cohort and 14 case-control studies containing 14,667 PC cases and 17,587 pancreatitis cases were included in this study. The pooled OR between pancreatitis and PC risk was 7.05 (95%CI: 6.42-7.75). Howeever, the pooled ORs of case-control and cohort studies were 4.62 (95%CI: 4.08-5.22) and 16.3 (95%CI: 14.3-18.6) respectively. The risk of PC was the highest in patients with chronic pancreatitis (pooled OR=10.35; 95%CI: 9.13-11.75), followed by unspecified type of pancreatitis (pooled OR=6.41; 95%CI: 4.93-8.34), both acute and chronic pancreatitis (pooled OR=6.13; 95%CI: 5.00-7.52), and acute pancreatitis (pooled OR=2.12; 95%CI: 1.59-2.83). The pooled OR of PC in pancreatitis cases diagnosed within 1 year was the highest (pooled OR=23.3; 95%CI: 14.0-38.9); and the risk in subjects diagnosed with pancreatitis for no less than 2, 5 and 10 years were 3.03 (95%CI: 2.41-3.81), 2.82 (95%CI: 2.12-3.76) and 2.25 (95%CI: 1.59-3.19) respectively. Pancreatitis, especially chronic pancreatitis, was associated with a significantly increased risk of PC; and the risk decreased with increasing duration since diagnosis of pancreatitis.

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“…The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).…”

mentioning

confidence: 99%

“…In this way, autophagy controls the cross-talk between the intracellular demand for energy, building blocks, and external stimuli (9). Autophagy is critically involved in mammalian development, cell survival, and longevity (10), and its impairment correlates with many pathological conditions (11), including pancreatitis (7). Notably, the mammalian exocrine pancreas exhibits a higher autophagy rate (or autophagic flux) than the liver, kidney, heart, or endocrine pancreas (12), underscoring the likely importance of autophagy in maintaining acinar cell homeostasis and function.…”

mentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

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

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195

172

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer

Cited by 289 publications

References 193 publications

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

Association Between Pancreatitis and Subsequent Risk of Pancreatic Cancer: a Systematic Review of Epidemiological Studies

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

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