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Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice
Author(s) -
Benesch Matthew G. K.,
Tang Xiaoyun,
Maeda Tatsuo,
Ohhata Akira,
Zhao Yuan Y.,
Kok Bernard P. C.,
Dewald Jay,
Hitt Mary,
Curtis Jonathan M.,
McMullen Todd P. W.,
Brindley David N.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-248641
Subject(s) - autotaxin , metastasis , breast cancer , cancer research , mammary tumor , cancer , extracellular , endocrinology , cell growth , lung cancer , medicine , receptor , chemistry , biology , lysophosphatidic acid , biochemistry
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; IC 90 =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.—Benesch, M. G. K., Tang, X., Maeda, T., Ohhata, A., Zhao, Y. Y., Kok, B. P. C., Dewald, J., Hitt, M., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB J . 28, 2655–2666 (2014). www.fasebj.org