Stopping the spread
 

From Al



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 http://www.nature.com/__chars/beta/b...base/glyph.gif1-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 http://www.nature.com/__chars/beta/b...base/glyph.gif1-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

1. Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006)
   
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Do you have the link for that. ( The GIF links dont seem to work by the way)

Is it the same LOX as in the eicosanoid pathway. see below

Sometime names can be confusing.

RB



http://www.ajcn.org/content/vol79/is...401780001.jpeg

I wish I understood this important stuff better. The only LOX I understand is what I eat with a bagel and cream cheese.

Sorry but me too!!!I really appreciate any news I see on here but although I don't consider myself a stupid person this is way over my head:)
Tricia

It took me a few times to read this looking up the various words as I read it. In reading this, it sounds like that there are 2 issues. One being that some tumors are hypoxic (oxygen deprived) and the second is that the LOX enzyme overexpression (produced by hypoxic tumors) is a growth agent for metasis.

If this is an accurate interpretation, then there would appear to be 2 possibilities for combating it. One would be to oxygenate the tumor. I believe that clinical trials are underway by Allos with efaproxirale to do this. The premise being that hypoxic tumors do not respond to chemo or radiation as well as oxygenated tumors. The second would be a LOX inhibitor. (The last sentence says that LOX would be a therapeutic agent; did that mean a LOX inhibitor?)

Is this how you interpret this?

Thanks for finding this. I am learning far more about this than I ever wanted to.

Thank you Susan2. Years ago I briefly did some science writing in which I tried to explain some University science projects in terms an unscientific 9th grader could understand. That's about my level when it comes to science. I appreciate what you did. I think I may take a crack at the next one.

You're welcome. I was helping my high school son with his anatomy a few weeks ago and so many of the words in his high school textbook I knew just from being on this website.

Hopefully, if we can work together to interpret these, they'll make more sense to us. I know that this makes me really want to push my children to become more science centered so that they have the skills to understand their own health.