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.

Keywords: cancer susceptibility; fatty infiltration; obesity; pancreatic cancer; type 2 diabetes mellitus.

Figure 1

Pancreatic fatty infiltration (FI) in humans and animals. Hematoxylin and eosin‐stained sections of the pancreas with intralobular FI and/or interlobular fat of pancreatic ductal adenocarcinoma (PDAC) patients (A‐D), Syrian golden hamsters at 24 wk of age (E), KK‐A ^y(F), KK (G), C57BL/6J‐A ^y (H), ICR (I) and C57BL/6J mice (J) at 17 wk of age, and OLETF (K) and LETO rats (L) at 65 wk of age that were obtained from our previous studies.18, 36, 39 Bar, 500 μm

Figure 2

N‐nitrosobis(2‐oxopropyl)amine (BOP)‐enhanced cell proliferation in pancreatic ducts (A) and common bile ducts (B) in KK‐A ^y mice. Modified from reference 58. KK‐A ^y, ICR, C57BL/6J and C57BL/6J‐A ^y mice were intraperitoneally injected with saline (white column) or BOP (black column) at a dose of 80 mg/kg of body weight, and the ratio of Ki‐67‐positive cells in pancreatic ducts (A) and common bile ducts (B) was examined 2 d later. In BOP‐treated KK‐A ^y mice, the enhancement of proliferation in both pancreatic (C) and common bile ducts (D) was observed, but not in BOP‐treated C57BL/6J mice (E,F).58 Data are the mean ± SD. *P < .05 and **P < .01 vs saline‐treated. Bar, 100 μm

Figure 3

Associations of age (A,B), body mass index (BMI) (C,D) and HbA1c (E,F) levels with pancreatic fatty infiltration (FI) areas in pancreatic cancer cases (n = 102) and controls (n = 85). The data were obtained from our previous study.18 Scatter plots of FI of the pancreas against age for cases (A) and controls (B), BMI for cases (C) and controls (D), and HbA1c for cases (E) and controls (F). r, Spearman's rank correlation coefficient

Figure 4

Association of pancreatic fatty infiltration (FI) with pancreatic ductal adenocarcinoma (PDAC). Modified from reference 18. The rate of severe FI (FI area ≥ 20%) is higher in PDAC cases than in the controls18

Figure 5

Involvement of fatty pancreas in pancreatic carcinogenesis. Modified from the figure in reference 16