Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma.

Chiaki Uchida,Hiroshi Yamamoto,Hiroki Mizukami,Kazuhiro Kudoh,Yasuhiko Yamamoto,Kenichi Hakamada,Yutaro Hara,Akiko Igawa,Takeshi Saito,Satoko Umetsu,Sho Osonoi,Soroku Yagihashi

doi:10.3390/ijms222111716

Abstract

Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with ≦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF−β and IL−6, but not from RAGE−deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease−free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.

Highlights

Pancreatic ductal adenocarcinoma (PDAC), one of the most difficult diseases in medicine, remains the fourth leading cause of cancer-related death worldwide [1,2]
Type 2 diabetes (T2D) often manifests as a part of metabolic syndrome, including obesity and dyslipidaemia, it is still unknown whether these metabolic disturbances are synergistically or involved in the activation of pancreatic stellate cells (PSCs) in PDAC
We evaluated the effects of abnormal glucose tolerance and metabolic syndrome on PSC activation in high fat diet (HFD)−induced obese (DIO) mice

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC), one of the most difficult diseases in medicine, remains the fourth leading cause of cancer-related death worldwide [1,2]. The stroma in PDAC, which can account for as much as 80–90% of the tumour mass, is partially associated with the proliferation of pancreatic stellate cells (PSCs). PSCs transform from quiescent cells to activated myofibroblast-like cells (MFCs) through various stimuli, including hyperglycaemia, obesity, and hyperinsulinaemia, in which secreted cytokines from activated PSCs promote tumour cell proliferation and invasion, metastasis, epithelial−mesenchymal transition (EMT) and resistance to chemotherapy [9,10,11,12,13,14,15,16,17,18,19]. T2D often manifests as a part of metabolic syndrome, including obesity and dyslipidaemia, it is still unknown whether these metabolic disturbances are synergistically or involved in the activation of PSCs in PDAC

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Results

Conclusion