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

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.

Arsenic trioxide-loaded nanoparticles enhance the chemosensitivity of gemcitabine in pancreatic cancer via the reversal of pancreatic stellate cell desmoplasia by targeting the AP4/galectin-1 pathway

“…The PDAC tissue is full of stromas as much as 80–90% of the tumor mass, which is mainly related to the proliferation of PSCs. 43 In order to verify this point, the pancreatic cancer tissues and normal adjacent tissues from 14 PDAC patients in Sun Yat-sen Memorial Hospital were collected and stained the proteins of α-SMA, collagen type I, and fibronectin expression related to the stroma matrix by immunohistochemistry. The results suggested that α-SMA, collagen type I, and fibronectin were expressed highly in most PDAC tissues (12/14) and weakly in para -tumor tissues (14/14) (Fig.…”

Diabetes mellitus impacts on expression of DNA mismatch repair protein PMS2 and tumor microenvironment in pancreatic ductal adenocarcinoma

“…Immunohistochemistry was performed with 4 μm thick sections of paraffin‐embedded tissue specimen as described elsewhere 1 , 20 , 21 . The slides were incubated at 4°C overnight with different primary antibodies shown in Table S1 .…”

“…Western blotting was performed as described previously. 21 The primary antibodies used in this study were shown in Table S1 .…”

“…Real‐time PCR was performed with cDNA generated from total RNA extracted from cell lysates as described previously 21 , 22 . Commercially available primer and probe sets were used (Gene Expression Assay, Thermo Fisher Scientific.)…”

Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology

“…Conditioned medium of AGE-stimulated PSCs induced epithelial-to-mesenchymal transition (EMT) in human pancreatic cancer cell lines, suggesting that RAGE signaling contributes to the cancer-promoting role of activated PSCs. The ratio of RAGE-positive cells correlated with the degree of α-SMA expression around pancreatic intraepithelial neoplasm, a precancerous lesion, found in surgically resected human pancreatic cancer specimens ( Uchida et al, 2021 ).…”