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Autotaxin and Tumor-Promoting Inflammation Open Access


Other title
mouse models
autotaxin inhibition
breast cancer
thyroid cancer
Type of item
Degree grantor
University of Alberta
Author or creator
Benesch, Matthew GK
Supervisor and department
Brindley, David N (Biochemistry)
McMullen, Todd PW (Surgery)
Examining committee member and department
Brindley, David N (Biochemistry)
Wuest, Frank (Oncology)
Baksh, Shairaz (Pediatrics)
Bourgoin, Sylvain (Laval University)
McMullen, Todd PW (Surgery)
Department of Biochemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through six G-protein-coupled receptors to promote cell survival, proliferation and migration. Knocking out autotaxin in mice is embryonically lethal as a result of impaired vasculogenesis and improper neural-crest folding. In the post-natal organism, autotaxin/ lysophosphatidate signaling mediates wound healing and tissue remodeling through acute inflammatory processes. However, in chronic inflammation, this signaling drives many diseases including rheumatoid arthritis, hepatitis, colitis, asthma and cancer. In cancer, lysophosphatidate promotes cell proliferation and migration, angiogenesis, metastasis and chemotherapy and radiotherapy resistance. Currently, there are no therapies targeting lysophosphatidiate signaling and this provides an opportunity for introducing new cancer treatments. Because most lysophosphatidate is produced by autotaxin activity, an inhibitor of the autotaxin catalytic site would block subsequent lysophosphatidate signaling. Therefore, it is important to understand how autotaxin activity is regulated by lysophosphatidate. It has been proposed that autotaxin is product-inhibited by lysophosphatidate or a related lipid called sphingosine-1-phosphate. This has led to the design of several lipid-mimetic autotaxin inhibitors. We now show that this competitive inhibition is ineffective at high concentrations of lysophosphatidylcholine that occur in vivo. Instead, lysophosphatidate and sphingosine-1-phosphate inhibit autotaxin expression through phosphatidylinositol-3-kinase activation. However, this physiological inhibition is overcome by inflammatory-mediated signaling. We propose that inflammation is vital for pathological autotaxin and lysophosphatidate production, and lysophosphatidate signaling in turn further drives an inflammatory environment. Consequently, an autotaxin inhibitor should be able to break this vicious cycle. However, this hypothesis has not been tested as historical autotaxin inhibitors have poor bioavailability profiles. We tested a novel non-lipid-mimetic ATX inhibitor (ONO-8430506) in mice which decreases plasma autotaxin activity by >80% and concentrations of unsaturated lysophosphatidates by >75% for 24 h. We also showed for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastasis in a 4T1/Balb/c syngeneic orthotopic breast cancer mouse model by 60% compared to vehicle-treatment. When combined with doxorubicin, ONO-8430506 synergistically decreases tumor growth and lung and liver metastases by >70%, whereas doxorubicin alone had marginal effects. Significantly, 4T1 breast cancer cells express neglible autotaxin compared to the mammary fat pad. Autotaxin activity in the fat pad of non-treated mice is increased 2-fold by tumor growth. This increase correlates with increases in inflammatory chemokine and cytokine production that is suppressed by ATX inhibition. We also extended our studies of autotaxin-mediated cancer growth and inhibition to papillary thyroid cancer. The diagnosis of thyroid cancer by fine needle biopsies is imprecise in ≥25% of cases resulting in unnecessary surgery. Many thyroid cancer patients also become resistant to radiotherapy and chemotherapy. Our work addresses both of these problems. We demonstrate that high expression of inflammatory chemokines and cytokines and increased secretion of autotaxin by thyroid cancer cells provides a definitive identification of human papillary thyroid cancer from benign nodules. Autotaxin secretion is hijacked in thyroid cancer in a vicious inflammatory cycle in which lysophosphatidate stimulates autocrine chemokine and cytokine secretion. This in turn increases autocrine autotaxin production. We show that treating mice daily with ONO-8430506 decreases thyroid tumor growth in xenograft models by >50%. There were also decreases in multiple inflammatory chemokines and cytokines, platelet-derived growth factor and vascular endothelial growth factor in the tumors. This results in decreased cancer cell division and angiogenesis. Therefore, regardless of whether autotaxin is produced in an autocrine fashion like in thyroid cancer or in a paracrine manner like in breast cancer, this work describes a new paradigm where autotaxin secretion is inflammatory-mediated and an autotaxin inhibitor is therapeutically effective. Autotaxin inhibitors have great potential to improve cancer patient outcomes and we propose that they also could have utility in other chronic inflammatory-mediated conditions.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Benesch, M.G.K., Ko, D., Tang, X., McMullen, T.P.W., and Brindley, D.N. (2014) Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions. (Review) FEBS Letters 588 (16), 2712-2727.Brindley, D.N., Benesch, M.G.K., and Murph, M.M. Autotaxin: An Enzymatic Augmenter of Malignant Progression Linked to Inflammation. (Review). In “Melanoma”, InTech. (Accepted August 25, 2014).Benesch, M.G.K., Tang, X., Maeda, T., Ohhata, A., Zhao, Y., Kok, B.P.C., Dewald, J., Hitt, M., Curtis, J.M., McMullen, T.P.W., and Brindley, D.N. (2014) Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB Journal 28 (6), 2655-2666.Venkatraman, G., Benesch, M.G.K., Tang, X., Dewald, J., McMullen, T.P.W., and Brindley, D.N. (2015) Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment. FASEB Journal 29 (3), 772-785.

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