title: Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.
abstract: Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO-8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle-treated mice. The effects of ONO-8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1-12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle-treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2-fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Exploration Research Laboratories, Ono Pharmaceuticals Company, Tsukuba, Japan; and.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceuticals Company, Shimamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohhata
authors.affiliation: Department of Agricultural, Food, and Nutritional Science.
authors.forename: Yuan Y
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry.
authors.forename: Bernard P C
authors.initials: BP
authors.lastname: Kok
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry.
authors.forename: Jay
authors.initials: J
authors.lastname: Dewald
authors.affiliation: Department of Oncology, and.
authors.forename: Mary
authors.initials: M
authors.lastname: Hitt
authors.affiliation: Department of Agricultural, Food, and Nutritional Science.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: Department of Surgery, Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, david.brindley@ualberta.ca.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D000099189:Lysophospholipase D
chemical_list: D002243:Carbolines; D008246:Lysophospholipids; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C000592118:ONO-8430506; C032881:lysophosphatidic acid
keywords: adipose tissue; lysophosphatidate; sphingosine 1-phosphate; syngeneic mouse model