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 status^{4, 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.

1. Department of Radiation Oncology,
2. Department of Surgery,
3. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
4. Department of Obstetrics and Gynecology, University of Leipzig, Leipzig 04103, Germany
5. Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27708, USA

Correspondence to: Amato J. Giaccia¹ Correspondence and requests for materials should be addressed to A.J.G. (Email: giaccia@stanford.edu).

Received 13 January 2006 | Accepted 2 March 2006

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