Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans

Abstract

Obesity, type 2 diabetes mellitus (T2DM) and aging are associated with pancreatic cancer risk, but the mechanisms of pancreatic cancer development caused by these factors are not clearly understood. Syrian golden hamsters are susceptible to N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic carcinogenesis. Aging, BOP treatment and/or a high‐fat diet cause severe and scattered fatty infiltration (FI) of the pancreas with abnormal adipokine production and promote pancreatic ductal adenocarcinoma (PDAC) development. The KK‐A y mouse, a T2DM model, also develops severe and scattered FI of the pancreas. Treatment with BOP induced significantly higher cell proliferation in the pancreatic ducts of KK‐A y mice, but not in those of ICR and C57BL/6J mice, both of which are characterized by an absence of scattered FI. Thus, we hypothesized that severely scattered FI may be involved in the susceptibility to PDAC development. Indeed, severe pancreatic FI, or fatty pancreas, is observed in humans and is associated with age, body mass index (BMI) and DM, which are risk factors for pancreatic cancer. We analyzed the degree of FI in the non‐cancerous parts of PDAC and non‐PDAC patients who had undergone pancreatoduodenectomy by histopathology and demonstrated that the degree of pancreatic FI in PDAC cases is significantly higher than that in non‐PDAC controls. Moreover, the association with PDAC is positive, even after adjusting for BMI and the prevalence of DM. Accumulating evidence suggests that pancreatic FI is involved in PDAC development in animals and humans, and further investigations to clarify the genetic and environmental factors that cause pancreatic FI are warranted.

Pancreatic Fat Infiltration Is Associated with a Higher Risk of Pancreatic Ductal Adenocarcinoma

“…Mechanistically, fatty pancreas may increase PDAC risk via tissue remodeling and fibroinflammatory reactions [15,16,28,36,44]. Fatty pancreas, a subclinical condition, may cause a chronic inflammatory state in the pancreas, due to increased proinflammatory cytokines and adipokines, i.e., pathways known to increase malignant transformation [13,14,[19][20][21].…”

Age‐related morphological changes in the pancreas and their association with pancreatic carcinogenesis

“…Furthermore, an association has been reported between focal fat replacement and pancreatic cancer . Reportedly, the degree of pancreatic fatty infiltration in patients with PDAC was significantly higher than that in non‐cancer controls . The association of PDAC and fat replacement was positive, even after adjusting for body mass index and the prevalence of DM, suggesting the involvement of fat replacement in PDAC development.…”

“…Arteriosclerosis and the consequent reduction in blood circulation may be a possible contributor. Various conditions are associated with fatty replacement including the overweight/obesity, the hypercholesterolemia, insulin resistance, type 2 DM, arterial hypertension and metabolic syndrome medications (steroids), alcohol, and genetic predisposition . With respect to the etiopathogenesis, it is likely that fatty replacement represents the terminal stage of gradual loss of exocrine tissue, which is focally prominent, without endocrine tissue involvement.…”

Precision Oncology in Pancreatic Cancer. From Surgery- to Genetic-Based Chemotherapy

“…Pancreatic ductal adenocarcinoma is one of the most lethal forms of solid tumors. These tumors arise from the exocrine component of the pancreas, probably from acinar stem cells [1][2][3] , and are characterized by an unusual amount of stroma, which includes a heterogenic assortment of cells, such as fibroblasts and immune and endothelial cells. The most important risk factors for this neoplasia are smoking and a family history of pancreatic tumors, but chronic pancreatitis, diabetes mellitus, obesity, and several new factors now being studied are also important 4 .…”