A44: Conjugated Bile Acids Accelerate Progression of Pancreatic Cancer Metastasis via S1PR2 Signaling in Obstructive Jaundice

Introduction: Obstructive jaundice is a sign of advanced pancreatic cancer. Conjugated bile acids that cause jaundice are now known not only as detergents for absorption of lipids, but also as signaling molecules which promote cell proliferation by binding to Sphingosine-1-Phosphate Receptor 2 (S1PR2). We hypothesize that bile acids as occurs in obstructive jaundice accelerate progression of metastatic pancreatic cancer via S1PR2.


Methods: Human pancreatic cancer AsPC-1, BxPC-3, and MiaPaca-2 and murine Panc02-luc and Panc-1 cell lines were used in a bile duct ligation (BDL) model.


Results: S1PR2 was the predominant S1P receptor in human AsPC-1 and murine Panc02-luc cells, and not in human BxPC-3 and MiaPaca-2 cells. Both CBA (taurocholate: TCA) and S1PR2 agonist (CYM5520) dependently stimulated cell growth of the AsPC-1 and Panc02-luc cells, but not of the other cells. This growth was completely inhibited by S1P antagonist (FTY-720). TCA significantly increased and JTE-013 completely inhibited cell migration by scratch assay consistently in both AsPC-1 and Panc02-luc cells. BDL that mimics obstructive jaundice significantly increased Panc02-luc cell liver metastasis compared to sham quantified by immunofluorescence. BDL also significantly increased the number of nodules, total tumor weight, rate of ascites in Panc02-luc peritoneal carcinomatosis model. Amount of peritoneal carcinomatosis was confirmed by live immunofluorescence imaging as well. In addition, Ki-67 staining of the nodules was significantly elevated in BDL compared to sham. Finally, BDL showed significantly shorter survival after Panc02-luc cell peritoneal dissemination compared to sham.


Conclusions: Conjugated bile acids increased growth of pancreatic cancer cell lines via S1PR2, which was the case in liver metastasis and peritoneal carcinomatosis in vivo. This is the first study to describe the effects of obstructive jaundice on the progression of pancreatic cancer in cells and in an animal model and suggests S1PR2 inhibition as a potential therapeutic target.