title: Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer.
abstract: Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined >200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four- to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1β, IL6, IL8, GMCSF, TNFα, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Yi M
authors.initials: YM
authors.lastname: Ko
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Jay
authors.initials: J
authors.lastname: Dewald
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Ana
authors.initials: A
authors.lastname: Lopez-Campistrous
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Yuan Y
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3 todd.mcmullen@albertahealthservices.ca david.brindley@ualberta.ca.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
authors.affiliation: Signal Transduction Research GroupDepartment of Biochemistry, 357 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2Department of Surgery2D4.41 WC Mackenzie Health Science Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5Department of Laboratory Medicine and PathologyUniversity of Alberta, Edmonton, Alberta, Canada T6G 2R3 todd.mcmullen@albertahealthservices.ca david.brindley@ualberta.ca.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D000099189:Lysophospholipase D
chemical_list: D018836:Inflammation Mediators; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid