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Cancer-spread enzyme 'found'

Monday 9 March 2009

Scientists have identified an enzyme that helps cancer spread around the body, the BBC reported. The Daily Express covered the same story with the headline “Cancer cure is step closer”. The newspaper said the enzyme, called LOX, is “crucial” in the spreading of cancer around the body. According to the report, the discovery will be used to develop drugs to block the enzyme, which is involved in preparing new areas for the cancer to invade.

This laboratory study provides greater insight into how cancer spreads. Given the early stage of the research, it will be some time before these findings are applied to cancer treatment in humans. But this does not diminish the importance of these findings, and more research will undoubtedly follow.

Where did the story come from?

Dr Janine T. Erler and colleagues from Stanford University School of Medicine, the Institute of Cancer Research and British Columbia Cancer Research Centre in Vancouver carried out this research. The study was published in the peer-reviewed medical journal Cancer Cell .

What kind of scientific study was this?

Over 90% of cancer-related deaths are due to metastatic disease, i.e. cancer that has spread to other parts of the body from the original cancer site. Previous research has shown that people with primary tumours that contain a high number of hypoxic (poorly oxygenated) tumour cells are more likely to have metastases. The researchers in this laboratory study aimed to further investigate the role of tumour hypoxia in the onset of cancer metastases.

The researchers say it is thought that ‘premetastatic niches’ form in the destination organs, which are favourable for the invasion and growth of tumour cells. These niches are made up of cell clusters that originally come from bone marrow (bone marrow-derived cells, BMDCs) and which encourage tumour growth and limit immune response through a range of mechanisms. How the BMDCs end up in premetastatic sites is not fully understood, but substances released by the primary tumour are thought to be involved.

One such substance is the enzyme lysyl oxidase (LOX), which appears in elevated levels in hypoxic tumours and is linked with metastases and poor survival rates from some cancers. In other laboratory studies, inhibition of LOX has been linked with reduced metastatic growth. The researchers in this study were interested in exploring exactly how LOX works, and in particular, if it plays a part in recruiting BMDCs to premetastatic sites.

The experiment involved implanting human breast tumour cells into mice. These included normal cancer cells and modified cancer cells containing a significantly reduced concentration of LOX enzyme. After six weeks, the mice lungs were removed and the number of secondary tumours between the two groups of mice were compared. The researchers also assessed the presence of various cells that indicate premetastatic sites and immune response at the lung site.

The researchers carried out further explorations into the exact effect of LOX on BMDCs in the lung. One experiment assessed whether it is LOX itself that is responsible for recruiting cells to pre-metastatic niches. This was investigated by injecting LOX secreted by tumour cells in a hypoxic medium into tumour-free mice for three weeks. In another experiment, LOX was purified and injected into mice to see what effect it had.

Another looked at how LOX promotes the involvement of BMDCs, while other complex in vitro studies explored the effects of LOX on the extracellular matrix in tissue. The researchers also looked at whether LOX recruited BMDCs in mice tissue other than the lungs, namely the liver and brain. Samples of metastatic tumours from humans were also examined for the presence of LOX and CD11b+ cells.

What were the results of the study?

After six weeks, mice with cancer that produced lower concentrations of LOX enzymes had fewer lung tumours than mice with unmodified human breast cancer cells. They also had evidence of fewer BMDCs, i.e. fewer premetastatic sites, particularly those containing CD11b+ cells (a particular type of white blood cell). Even in the absence of tumours (i.e. in cancer-free mice), injection with a culture medium that contained LOX from hypoxic cancer cells resulted in higher concentrations of CD11b+ cells in the lungs (premetastatic sites).

Purified LOX did not have as great an effect as LOX in the presence of hypoxic tumour cells. LOX appeared to establish cross-links between collagens and elastins (a type of protein). LOX and CD11b+ cells were found in samples of metastatic tumours from the brain, liver, neck, ovary, lymph nodes and omentum tissue (a layer of fat in the abdomen).

What interpretations did the researchers draw from these results?

The results suggest that inhibiting LOX enzymes decreases tumour cell invasion and metastases, and that LOX plays a role in establishing premetastatic sites in lung tissue. LOX is secreted by the primary tumour, and it binds to a protein (fibronectin) in sites of future metastases. The enzyme cross-links collagen, and recruits CD11b+ cells to establish premetastatic sites. The researchers say that this data supports “targeting hypoxia-induced secreted LOX for the treatment and prevention of metastatic cancer”.

What does the NHS Knowledge Service make of this study?

This laboratory study gives further insight into how cancer spreads from primary sites to secondary organs. If metastases can be discouraged by targeting the compounds involved in establishing premetastatic sites, then there is potential for reducing the spread of cancers, which is a major cause of death in cancer patients. However, this research is at an early stage. It will be some time before it is known whether these findings have an application for treating cancers in living humans.

Dr. Julie Sharp from Cancer Research UK has said that the research has taken scientists a step closer to understanding this major problem, and that “the next stage will be to find out if the LOX protein can be switched off to stop cancer spreading”.

Analysis by Bazian
Edited by NHS Website

Links to the science

Erler JT, Bennewith KL, Cox TR, et al.

Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche.

Cancer Cell 2009; 1; 35-44