Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell–cell or cell–matrix interactions) and the extended tumour microenvironment (for example vascularization)1. Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear2. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells3. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status4,5,6,7,8,9. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.
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We thank P. Chu (immunohistochemistry), D. Menke (tail-vein injections), R. Nacamuli (quantitative polymerase chain reaction), R. R. Balise (statistical programming) and C. Davis (board-certified veterinary pathologist); N. Quach (FAK, phospho-FAK and F-actin antibodies), A. Cress (α6 antibody), P. Marinkovich (β1 integrin antibody) and D. Mosher (FN-null cells) for supplying reagents; and P. Friedl, Z. Werb and P. Steeg for discussions. All animal work was performed in accordance with the Stanford University Administrative Panel for Laboratory Animal Care. This research was supported by funds from the NIH (J.T.E. and A.J.G.), the Canadian Institutes of Health Research (K.L.B.), the Else Kröner-Fresenius-Foundation (N.D.) and the California Breast Cancer Research Program (S.S.J.). Author Contributions J.T.E., A.J.G. and S.S.J. conceived and designed the experiments. J.T.E. performed the experiments with the assistance of K.L.B. and N.D. for in vivo work. J.T.E., A.J.G., M.N., J.T.C. and S.S.J. analyzed the data. J.T.E. wrote the paper with the assistance of K.L.B., S.S.J. and A.J.G. The head and neck cancer study was performed by Q.T.L. and C.K.
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Journal of Analysis and Testing (2019)