title: Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.
abstract: Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX.
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jay
authors.initials: J
authors.lastname: Dewald
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Dong
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Denise G
authors.initials: DG
authors.lastname: Hemmings
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
authors.affiliation: *Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada david.brindley@ualberta.ca.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000473:pathology; D042361:Mammary Glands, Human / Q000201:enzymology* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D000099189:Lysophospholipase D
chemical_list: D009363:Neoplasm Proteins; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D
keywords: chemokines; cytokines; lysophosphatidate; syngeneic mouse model; tumor stroma