What to fear most if faced by a cancer diagnosis is the spread of the cancer to other parts of the body. This process called metastasis accounts for over 90% of cancer patient deaths and therefore is a strong focus for cancer researchers. Researchers at BRIC, University of Copenhagen have shown that the enzyme Lysyl Oxidase (LOX) can create a "scarred" microenvironment that enhances cancer spreading. By blocking activity of the LOX enzyme, the researchers succeeded in significantly decreasing metastasis in a model of breast cancer.
'When we inhibit the activity of LOX in our cancer models, we show a dramatic reduction in metastasis. This suggests that therapeutic targeting of LOX can keep the tumour microenvironment "healthy" and thereby decrease metastasis, says Associate Professor Janine Erler from BRIC, who has headed the research.
LOX -- A link between tissue scarring and metastasis
In humans, LOX is an enzyme that is produced in response to tissue injury or chronic inflammation in our organs. It reacts to damage signals and "glues" collagen molecules together to form the scar-like structure. The result can be a fibrotic environment. The new findings from Janine Erler's research group show that persistent injury to lung and liver results in a fibrotic microenvironment that supports the growth of new tumours, and thereby enhances metastasis of breast cancer cells to these organs. Blocking LOX prevents the formation of this fibrotic microenvironment, thereby preventing enhanced metastasis to these organs.
'It is well-known that signals from fibrotic tissues can enhance tumour progression and metastasis, but the underlying mechanisms have remained unclear -- Our new results provide insight into the link between fibrosis and cancer progression. Such a biological understanding is crucial if we are to develop effective therapies preventing tumour metastasis, says PostDoc Thomas Cox from Janine Erler's laboratory, who undertook the experimental investigation.
Development of new anti-fibrotic therapies
Currently, LOX-targeting therapies are under development for use in the clinic against cancer, as it has been known for some while that metastatic tumours express increased amounts of LOX. Yet, the new results from Janine Erler's group are the first to show that LOX promotes distant metastasis through structural changes in the organ microenvironments in response to persistent injury. The next step for the researchers is to dig deeper into the mechanisms underlying the relationship between fibrosis and cancer metastasis, and also to test their findings in other cancer models such as gastric and colon cancer.
'Further, our study indicates that LOX-targeting therapy can be relevant not only for cancer patients, but also to prevent fibrosis in patients with chronic inflammation or patients who has been exposed to persistent organ injury. This opens up for an even wider applicability of our biological findings, which strongly motivates the basic research in my laboratory, says Janine Erler.
The results have just been published in the international journal Cancer Research. The work was initiated at the Institute of Cancer Research UK and completed at BRIC. The work has been supported by research grants from the Cancer Research UK and the Novo Nordisk Foundation.
- T. R. Cox, D. Bird, A.-M. Baker, H. E. Barker, M. W.-Y. Ho, G. Lang, J. T. Erler. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Research, 2013; DOI: 10.1158/0008-5472.CAN-12-2233
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