Obesity and Pancreatic Cancer: Insight into Mechanisms

Abstract

The prevalence of obesity in adults and children has dramatically increased over the past decades. Obesity has been declared a chronic progressive disease and is a risk factor for a number of metabolic, inflammatory, and neoplastic diseases. There is clear epidemiologic and preclinical evidence that obesity is a risk factor for pancreatic cancer. Among various potential mechanisms linking obesity with pancreatic cancer, the adipose tissue and obesity-associated adipose tissue inflammation play a central role. The current review discusses selected topics and mechanisms that attracted recent interest and that may underlie the promoting effects of obesity in pancreatic cancer. These topics include the impact of obesity on KRAS activity, the role of visceral adipose tissue, intrapancreatic fat, adipose tissue inflammation, and adipokines on pancreatic cancer development. Current research on lipocalin-2, fibroblast growth factor 21, and Wnt5a is discussed. Furthermore, the significance of obesity-associated insulin resistance with hyperinsulinemia and obesity-induced gut dysbiosis with metabolic endotoxemia is reviewed. Given the central role that is occupied by the adipose tissue in obesity-promoted pancreatic cancer development, preventive and interceptive strategies should be aimed at attenuating obesity-associated adipose tissue inflammation and/or at targeting specific molecules that mechanistically link adipose tissue with pancreatic cancer in obese patients.

The relationship between pancreatic cancer and type 2 diabetes: the Fremantle Diabetes Study Phase I

“…In the case of diabetes‐specific risk factors, our 15.5% increase in pancreatic cancer risk per mmol/L increase in fasting plasma glucose in our participants with type 2 diabetes is identical to that found in a recent meta‐analysis 14 . Sustained basal hyperglycaemia is a likely surrogate for increased insulin resistance which can stimulate a range of tumour‐promoting molecular pathways 15 . Persistently high fasting blood glucose levels relative to the contemporaneous HbA 1c could thus represent a simple laboratory risk indicator.…”

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway

“…Pancreatic ductal cancers are relatively uncommon, difficult to detect, and frequently diagnosed at an advanced stage with low survival rates due to reduced effective treatment options [185,186]. Chronic inflammation, attributable to obesity, diabetes, diet, and pancreatitis, usually precedes pancreatic cancers [187,188]. Extensive studies have focused on SphK/S1P/S1PR and insulin signalling in pancreatic beta cells due to their importance in inflammation, insulin resistance, and diabetes [189,190].…”

Pancreatic Cancer and Microenvironments: Implications of Anesthesia

“…Obesity-associated adipose tissue inflammation may play a central role in the development of PC and the promotion of PC growth [ 32 ]. Chronic inflammation, hormonal effects, circulating adipokines, and adipocyte-mediated inflammatory and immunosuppressive microenvironments are involved in the association of obesity with PC [ 33 ].…”

“…Recently, Zorbas et al showed that obesity was significantly associated with higher risk of postoperative complications and mortality in patients with body mass index ≥ 40 after pancreatoduodenectomy [ 38 ]. Obesity-associated adipose tissue inflammation may play a central role in the development of PC and the promotion of PC growth [ 32 ]. Thus, anesthetics with the effect of inhibiting obesity-induced inflammation may improve postoperative outcomes [ 35 ].…”