Irreversible and sustained upregulation of endothelin axis during oncogene-associated pancreatic inflammation and cancer.
Endothelin-1 (ET-1) and its two receptors, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) exhibit deregulated overexprerssion in pancreatic ductal adenocarcinoma (PDAC) and pancreatitis. We examined the expression pattern of endothelin (ET) axis components in the murine models of chronic and acute inflammation in the presence or absence of oncogenic K-ras. While the expression of endothelin converting enzyme-1 (ECE-1), ET-1, ETAR and ETBR in the normal pancreas is restricted predominantly to the islet cells, progressive increase of ET receptors in ductal cells and stromal compartment is observed in the KC model (Pdx-1 Cre; K-rasG12D) of PDAC. In the murine pancreas harboring K-rasG12D mutation (KC mice), following acute inflammation induced by cerulein, increased ETAR and ETBR expression is observed in the amylase and CK19 double positive cells that represent cells undergoing pancreatic acinar to ductal metaplasia (ADM). As compared to the wild type (WT) mice, cerulein treatment in KC mice resulted in significantly higher levels of ECE-1, ET-1, ETAR and ETBR, transcripts in the pancreas. Similarly, in response to cigarette smoke-induced chronic inflammation, the expression of ET axis components is significantly upregulated in the pancreas of KC mice as compared to the WT mice. In addition to the expression in the precursor pancreatic intraepithelial neoplasm (PanIN lesions) in cigarette smoke-exposure model and metaplastic ducts in cerulein-treatment model, ETAR and ETBR expression is also observed in infiltrating F4/80 positive macrophages and α-SMA positive fibroblasts and high co-localization was seen in the presence of oncogenic K-ras. In conclusion, both chronic and acute pancreatic inflammation in the presence of oncogenic K-ras contribute to sustained upregulation of ET axis components in the ductal and stromal cells suggesting a potential role of ET axis in the initiation and progression of PDAC.
['Gupta|Suprit|S|', 'Prajapati|Avi|A|', 'Gulati|Mansi|M|', 'Gautam|Shailendra K|SK|', 'Kumar|Sushil|S|', 'Dalal|Vipin|V|', 'Talmon|Geoffrey A|GA|', 'Rachagani|Satyanarayana|S|', 'Jain|Maneesh|M|']
D000681:Amylases D000818:Animals D002108:Ceruletide D004195:Disease Models, Animal D019332:Endothelin-1 D000072396:Endothelin-Converting Enzymes D005786:Gene Expression Regulation D006801:Humans D007249:Inflammation D051379:Mice D009857:Oncogenes D010190:Pancreatic Neoplasms D010195:Pancreatitis D016283:Proto-Oncogene Proteins p21(ras) D044022:Receptor, Endothelin A D044023:Receptor, Endothelin B
Endothelin Pancreatitis Oncogenic K-ras PanIN lesions Acinar-ductal metaplasia Pancreatic injury Precancerous lesions