Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive carcinoma with poor prognosis. Its poor prognosis is ascribed to the extensive fibrotic stroma. Pancreatic stellate cells (PSCs) are major contributors to PDAC fibrosis. Type 2 diabetes (T2D) is an established risk factor for PDAC. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs) and the signaling through receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Nevertheless, the role of RAGE in PSCs activation was not evaluated in PDAC with T2D. First, PSCs were isolated from male obese T2D model, db/db (db) and db/m (C) mice at 12 weeks of age. mRNA expression of the makers for PSCs activation like TGF-β1, αSMA and collagen type1A1 were significantly increased in PSCs isolated from db compared to C (p<0.01, respectively). To evaluate the implication of RAGE, PSCs isolated from C57BL/6 (WT) and RAGE deleted mice (RKO) were stimulated with 12.5-100 μg/ml AGEs. AGEs increased mRNA expression of TGF-β1, αSMA and collagen type1A1 in WT-PSCs with dose dependent manner (p<0.01, respectively) despite no increase in mRNA expressions in RKO-PSCs. Furthermore, PSCs were isolated from high fat diet induced obese WT and RKO for 8 weeks. The mRNA expressions of TGF-β1, αSMA and collagen type1A1 were comparable between two groups. We evaluated surgically resected human PDAC subjects with T2D (PDT2D, 33 cases) and without T2D (PDNT2D, 83cases). αSMA-labeled PSCs significantly surrounded the ducts with dysplasia in PDT2D compared to PDNT2D (p<0.05). The nuclear expression of NF-κB in stromal cells, which was downstream molecules of RAGE, was significantly higher in PDT2D than PDNT2D (p<0.05). Collectively, RAGE signaling was activated in PSCs in T2D, which could be implicated in severe stromal fibrosis in PDAC. Inhibition of RAGE signaling in PSCs may link to a new therapy, in which the stromal fibrosis and cytokine production are reduced in PDAC with T2D.
C. Uchida: None. H. Mizukami: None. K. Kudo: None. Y. Yamamoto: None.
Japan Society for the Promotion of Science (JP17K17579)