Lysyl oxidase is essential for hypoxia-induced metastasis.
Published
Journal Article
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). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. 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. 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.
Full Text
Duke Authors
Cited Authors
- Erler, JT; Bennewith, KL; Nicolau, M; Dornhöfer, N; Kong, C; Le, Q-T; Chi, J-TA; Jeffrey, SS; Giaccia, AJ
Published Date
- April 27, 2006
Published In
Volume / Issue
- 440 / 7088
Start / End Page
- 1222 - 1226
PubMed ID
- 16642001
Pubmed Central ID
- 16642001
Electronic International Standard Serial Number (EISSN)
- 1476-4687
Digital Object Identifier (DOI)
- 10.1038/nature04695
Language
- eng
Conference Location
- England