Breast cancer 'tumour trigger' that spreads disease discovered

“Experts have identified a ‘trigger’ which enables breast cancer cells to spread,” the Daily Mirror reports. The trigger – a protein called CCL3 – appears to help cancerous cells spread into the lungs. The hope is that targeting the protein could help prevent any spread and reduce the number of deaths from breast cancer.

Scottish-based researchers found specific chemical signals and receptors on immune cells called macrophages that were orchestrating some of the spread of cancer. By genetically tampering with a protein involved in the process, they were able to reduce some of the spread and growth of cancer, raising hopes that this might be a future treatment avenue.

Tampering with the genetics in the same way as the mice would not be a viable human treatment. The protein is common, so disrupting it may cause side effects. However, there are potentially other ways of blocking it more specifically, such as new targeted drugs, so this research could lead to new treatment options.

The study didn’t tell us whether the mice lived longer, experienced less pain or responded better to other treatments. It should also be noted that cancer spread was not completely halted, just reduced. Therefore, we don’t know whether this approach would benefit humans.

This is a positive development in the understanding of how cancer spreads and becomes more life-threatening, but there are no immediate treatment implications.

Where did the story come from?

The study was carried out by researchers from the University of Edinburgh and Albert Einstein College of Medicine, New York. It was funded by the United States Department of Defence, US National Institutes of Health grants, and the Wellcome Trust (UK).

The study was published in the Journal of Experimental Medicine, a peer-reviewed medical journal.

Generally, the UK media reported the story accurately, suggesting that the new discovery offered hope, rather than anything more concrete or immediate. Most said the research was carried out on mice, but few explained how this might limit the relevance of the results on humans.

What kind of research was this?

This was a laboratory study looking to better understand how breast cancer spreads to the lungs in mice.

Breast cancer is the most common cancer in the UK. The lifetime risk of being diagnosed with breast cancer is 1 in 8 for women in the UK. While survival rates are generally high compared to other cancers – almost 8 out of 10 women diagnosed will survive for at least 10 years after a diagnosis – there are still many deaths. This, the research tells us, is mainly due to the breast cancer cells spreading to other parts of the body – called metastatic cancer.

Macrophages are cells of the immune system that seek and destroy things like cell debris and bacteria. They recognise proteins on the surface of cells. If recognised as safe, they leave them alone, but if recognised as a threat, they attempt to engulf and digest the foreign body.

There are a large number of clinical studies, the researchers’ say, that indicate a strong correlation between poor prognosis of breast cancer and high infiltration of macrophages in the tumour. They thought the macrophages were helping the tumour spread from the breast to other parts of the body, particularly the lungs.

To investigate the role of macrophages, the researchers used mice genetically engineered to develop breast cancer. Using mice versions of human diseases is a useful way to better understand the disease processes and look for cures without putting humans at risk. Any positive findings will eventually be tested in humans, as the results in mice are not always the same. This is because the disease and underlying biology of the mammals can differ in important ways.

What did the research involve?

The researchers used mice specially bred to develop breast cancer, to mimic the human disease. The research team studied the genetic and chemical signals involved in breast tumour development and its spread to the lungs. They also documented the behaviour and biochemistry of immune cells involved in the processes, such as macrophages.

Macrophages, like many other immune cells, respond to a range of external chemical signals that bind to receptors on their surface. This can stimulate them into developing in different ways, and tell them where to go and what to do. Some chemical signals cause the release of more signalling molecules, resulting in a cascade of chemical commands. The result could be to signal more macrophages to the area, or command them to grow and divide. These complex webs of chemical communication are often referred to as signalling pathways.

Using standard genetic manipulation techniques, they were able to delete key parts of the cancer signalling pathway to see what would happen. By switching on and off different signalling pathways, and points in the pathways, they slowly built up a better understanding about what was going on.

What were the basic results?

They found that macrophages were attracted to the breast cancer tumour and some were involved in helping the tumour spread to the lungs. These macrophages were changed by the tumour and were called “metastasis-associated macrophages (MAMs)”.

The researchers discovered that these MAMs then responded to chemical signals linked to the tumour, called cytokines, receiving these signals through receptors in their cell membranes. Stimulation from cytokine CCL2 increased the number of MAMs. These MAMs then secreted cytokine CCL3, which further increased the number of MAMs at the site of the metastases – in this case, the lungs.

Using genetic manipulation, the scientists deleted various receptors in this chain, so the MAMs could no longer respond to these particular signals. This reduced the number of tumour cells spreading to the lungs and reduced the growth of metastases, suggesting that this particular signalling pathway was important in the process.

How did the researchers interpret the results?

They concluded that drugs targeted at inhibiting the CCR1 receptor that is stimulated by the CCL3 at the site of metastases could reduce the impact of the macrophages and “may have a therapeutic impact” in metastatic breast cancer, with less side effects. This is because the drugs would target MAMs rather than normal macrophages. They say that attempts to block earlier stages of this complex pathway have been shown to impair the immune system, reducing the ability to fight infection.

Conclusion

An Edinburgh-based team used mice engineered to develop breast cancer to better understand how it spreads from breast tissue to the lung, where it can be fatal. They identified specific chemical signals and receptors on immune cells called macrophages that were involved in the spread. By genetically tampering with one of the signalling pathways, they were able to reduce some of the cancer spread, raising hopes that this might be a future treatment avenue.

Fiddling with the genetics in the same way as was done for the mice would probably not be a viable treatment for humans. Aside from ethical and technical issues, genetic manipulation of this nature could lead to a range of side effects.

However, there are potentially other ways of blocking the same signalling pathway.

The results were encouraging, but they are at a very early research stage. Right now, we don’t know if this would work in humans, because it has only been tested in mice. While biologically similar, mice and humans do differ in potentially important ways. The only way to know if disrupting this signalling pathway might be useful in minimising breast cancer spread to the lungs would be to do experiments on humans.

We also don’t know if this treatment helped the mice live longer, experience less pain or respond better to other treatments. Similarly, the genetic manipulation didn’t stop the cancer spreading completely to the lungs, it just reduced it. Hence, we are a long way off stopping the spread totally, but it is a step in the right direction.  

Links To The Headlines

Breast cancer ‘stopped from spreading in body’ as new study gives hope to patients. Daily Mirror, June 9 2015

Breast cancer breakthrough after scientists find trigger that causes disease to spread to the lungs: Discovery will pave way for life-saving new drugs. Mail Online, June 9 2015

Breast cancer spread ‘trigger’ discovered. The Guardian, June 8 2015

Scientists discover ‘trigger’ which could stop breast cancer spreading. The Daily Telegraph, June 9 2015

New hope on breast cancer therapy. Scottish Express, June 9 2015

Links To Science

Kitamura T, Qian B, Soong D, et al.CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. The Journal of Experimental Medicine. Published online June 8 2015