Autotaxin and Tumor-Promoting Inflammation

  • Author / Creator
    Benesch, Matthew GK
  • 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.

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  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.