Biology of the PancreasReviewInflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer
Section snippets
Role of Inflammation in Pancreatitis
The initial injury that causes AP results in acinar cell necrosis and an inflammatory response, which are usually sterile.7 In most patients, the acute inflammatory response and pancreas damage ultimately resolve, but in severe cases unremitting SIRS leads to multiple organ (especially lung) failure, a major cause of mortality among patients with AP.8, 9, 10, 11 Twenty years ago, patients with AP were reported to have increased levels of circulating inflammatory cytokines.12, 13 Studies of
Inflammation in PDAC Development
PDAC is the most common type of pancreatic cancer and is notable for its aggressiveness, desmoplastic stromal response, immunosuppression, and resistance to therapies.90, 91, 92, 93 Two types of inflammation contribute to PDAC initiation and progression. One is chronic inflammation caused by pancreatitis, obesity, or other genetic or environmental factors, and the other is tumor-associated inflammation. A typical feature of PDAC is its abundant desmoplasia, which comprises extracellular matrix
The Process of Autophagy
Autophagy comprises several intracellular pathways of lysosome-mediated degradation and recycling of organelles, long-lived proteins, and lipids.110, 111 Macroautophagy (hereafter referred to as autophagy) begins with the formation of an autophagosome, a unique double-membrane vacuole that sequesters material destined for degradation. Autophagosome formation is a complex process controlled by evolutionary conserved autophagy related (ATG) proteins.111, 112 Autophagosomes fuse with lysosomes,
Impaired Autophagy in Pancreatitis
The role of autophagy in pancreatitis recently was discussed in detail (see article by Gukovskaya and Gukovsky116). Evidence from animal models indicates that autophagy is impaired in pancreatitis, and that one mechanism involves defective functions of lysosomes. A hallmark of impaired autophagy is the accumulation of abnormally large vacuoles. Acinar cell vacuolation is a long-noted but poorly understood feature of experimental and human pancreatitis.117, 118, 119, 120, 121, 122 Most of these
Roles for Autophagy in PDAC Development
Autophagy is believed to have different roles during different stages of cancer development (Figure 3), suppressing tumorigenesis but promoting growth of established tumors.138, 139, 140 PDAC cells require autophagy to survive stressful conditions, such as hypoxia, nutrient deprivation, metabolic stress, and chemotherapy.138 They have higher basal levels of autophagy than other types of tumor cells, possibly owing to Kras activation.141 However, this makes PDAC cells more sensitive to
Defects in Autophagy Promote Inflammation
Autophagy limits inflammation whereas defects in autophagy could mediate the pathogenesis of inflammatory diseases.110, 159 Defective autophagy can promote inflammation through several mechanisms (Figure 4), in particular by activating specific transcriptional responses. For example, p62 accumulation in autophagy-deficient cells leads to TRAF6 oligomerization and NF-κB activation.99, 128 Importantly, the combined activation of NF-κB by Ras and p62 promotes pancreatic tumorigenesis.99
Leaky or
Obesity Predisposes to Pancreatic Disorders by Affecting Inflammation and Autophagy
The obesity epidemic is a growing threat to human health, worldwide.162, 163 It is the most common cause of insulin resistance and greatly increases the risk for cardiovascular disease, stroke, and some types of cancer. Obesity increases susceptibility to these diseases by causing low-grade chronic inflammation.162, 163, 164, 165 The links between obesity and inflammation are not fully understood, but several mechanisms have been proposed. The expansion of fat mass, caused by adipocyte
Summary and Future Directions
Inflammation and defective autophagy are each involved in the pathogenesis of pancreatitis and pancreatic cancer, and mediate the effects of obesity in promoting exocrine pancreatic diseases. The severity of AP is largely determined by whether the inflammatory response resolves or amplifies into persistent SIRS and multiple organ failure. Chronic low-grade inflammation promotes fibrosis and cell death during progression of CP.
Although our knowledge of the mechanisms of inflammation in
Acknowledgments
The authors apologize to many authors whose studies could not be cited because of space limitations.
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Funding Our research was supported by the Department of Veterans Affairs and National Institutes of Health grants DK59936, and, in part, P01 CA163200 (A.G.), AA19730 (I.G.), AI043477 (M.K.), CA163798 (M.K.), P50 AA011999 (A.G, I.G, Pilot Project to M.K.), and R03CA167120 (N.L.), by a Pancreatic Cancer Research Lustgarten Foundation grant RFP-B-007 (M.K.), and the Erwin Schrödinger Fellowship J 3233 of the Austrian Science Fund (J.T.).