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

• Published in: International journal of molecular sciences Vol. 22; no. 21; p. 11716
• Main Authors: Uchida, Chiaki, Mizukami, Hiroki, Hara, Yutaro, Saito, Takeshi, Umetsu, Satoko, Igawa, Akiko, Osonoi, Sho, Kudoh, Kazuhiro, Yamamoto, Yasuhiko, Yamamoto, Hiroshi, Yagihashi, Soroku, Hakamada, Kenichi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.10.2021; MDPI
• Subjects: Actins - metabolism; Adenocarcinoma; advanced glycation end products; Advanced glycosylation end products; Age; Animals; Cancer; Carcinoma, Pancreatic Ductal - complications; Carcinoma, Pancreatic Ductal - metabolism; Cell culture; Culture; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diet, High-Fat - adverse effects; EMT; Epithelial-Mesenchymal Transition; Evaluation; Glucose; Glycation End Products, Advanced - metabolism; Glycosylation; High fat diet; Humans; Insulin; Mesenchyme; Metabolic disorders; Metabolic syndrome; Mice; Mice, Inbred C57BL; Pancreas; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Intraductal Neoplasms - metabolism; Pancreatic Neoplasms - complications; Pancreatic Neoplasms - metabolism; Pancreatic Stellate Cells - metabolism; Pathophysiology; Primary Cell Culture; RAGE; Receptor for Advanced Glycation End Products - metabolism; Stellate cells; type 2 diabetes; metabolic syndrome; type 2 diabetes; RAGE; EMT; advanced glycation end products; pancreatic ductal adenocarcinoma
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222111716

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.