Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer.
Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. 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.
['Jinno|Naruomi|N|https://orcid.org/0000-0002-2634-2338', 'Yoshida|Michihiro|M|https://orcid.org/0000-0002-4167-2781', 'Hayashi|Kazuki|K|https://orcid.org/0000-0001-5217-2873', 'Naitoh|Itaru|I|https://orcid.org/0000-0001-8342-886X', 'Hori|Yasuki|Y|https://orcid.org/0000-0001-9510-2568', 'Natsume|Makoto|M|https://orcid.org/0000-0002-1716-0583', 'Kato|Akihisa|A|https://orcid.org/0000-0002-7733-7854', 'Kachi|Kenta|K|https://orcid.org/0000-0001-7462-7170', 'Asano|Go|G|https://orcid.org/0000-0002-1528-7572', 'Atsuta|Naoki|N|https://orcid.org/0000-0002-3563-0614', 'Sahashi|Hidenori|H|https://orcid.org/0000-0003-3983-593X', 'Kataoka|Hiromi|H|https://orcid.org/0000-0001-9491-0723']
D000818:Animals D001201:Ascites D021441:Carcinoma, Pancreatic Ductal D005260:Female D064593:Heterografts D006801:Humans D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009361:Neoplasm Invasiveness D010190:Pancreatic Neoplasms D010534:Peritoneal Neoplasms D010727:Phosphoric Diester Hydrolases
autotaxin peritoneal dissemination pancreatic cancer malignant ascites molecular targeted therapy