Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer

概要

Pancreatic ductal adenocarcinoma (PDAC) is well-known as one of the cancers with the poorest prognosis, and the 5-year survival rate is reported to be less than 5%. Peritoneal dissemination and malignant ascites in PDAC patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates various cancer progression. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on Autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX- LPA axis in malignant ascites in PDAC, and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380. An in vivo study showed that PF-8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC.