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Research Highlight
Nature Reviews Cancer 6, 417 (June 2006) | doi:10.1038/nrc1914
Metastasis: Stopping the spread
Sarah Seton-Rogers
Hypoxic conditions have been correlated with both metastasis and poor outcome in cancer patients. Amato Giaccia and colleagues have now shown that the enzyme lysyl oxidase (
LOX), which is highly expressed in hypoxic tumour cells, is crucial for hypoxia-induced metastasis.
The LOX enzyme is important for extracellular matrix (ECM) formation. It oxidizes lysine residues in collagen and elastin, therefore stabilizing and strengthening the fibres. This, combined with the expression of LOX in hypoxic tumour cells, led Giaccia and colleagues to propose that LOX might be involved in remodelling the ECM to promote metastasis.
The authors first showed that LOX expression is regulated by the transcription factor hypoxia-inducible factor 1 (
HIF1) in human cancer cell lines. They then used mouse models to confirm a role for LOX in promoting metastasis. Decreasing LOX expression with LOX short-hairpin RNA (shRNA) in the MDA231 breast cancer cell line decreased the incidence of metastasis when the cells were grown as orthotopic tumours in nude mice. In addition, mice with MDA231 tumours that were treated with a specific LOX inhibitor or an anti-LOX antibody had fewer metastases, which demonstrates the therapeutic potential of inhibiting LOX.
How does LOX induce metastasis? Hypoxia-induced invasion of several cancer cell lines in vitro was reduced by LOX inhibition. The LOX enzyme can function both intracellularly and extracellulary, but only inhibition of extracellular LOX reduced invasion, and conditioned medium from cells that expressed LOX increased invasion. Cell migration, which is required for invasion, was also reduced in LOX shRNA MDA231 cells. So, mechanistically, how might extracellular LOX affect cellular motility and invasion?
Cell migration requires several processes such as the formation of pseudopodia at the leading edge, and activation of integrin ECM receptors and downstream signalling pathways that regulate the actin cytoskeleton and ECM remodelling. One role of LOX is to increase collagen fibre formation in the ECM. The authors proposed that collagen, which is a ligand for
1-integrin, might increase cell motility through the activation of focal adhesion kinase (
FAK). Indeed, LOX shRNA cells had a reduced level of phosphorylated FAK, and LOX transfection restored FAK phosphorylation, which could in turn be blocked by
1-integrin-inhibiting antibodies. Immunofluorescent staining of extracellular LOX was observed at the leading edge of MDA231 cells, particularly under hypoxic conditions, which provides further evidence that LOX might promote metastasis through remodelling the ECM.
Giaccia and colleagues also showed that increased expression levels of LOX correlated with decreased survival in patients with
breast cancer or
head and neck cancer, a finding that further supports LOX as a therapeutic target to prevent metastasis.
References and links
ORIGINAL RESEARCH PAPER
- Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006)
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