Sowing the ‘seed’ of cancer spread

Researchers are investigating how the 'seeds' of cancer are spread to the brain

One of the biggest challenges of cancer treatment – and cancer research – is working out how to block metastasis – the spread of cancer around the body.

In fact, most people who die of cancer die because the disease spreads to – and interferes with – other organs than the one in which the cancer originally started.

Many researchers around the world are trying to understand why and how cancer spreads, with the aim of finding ways to prevent it, or treat secondary tumours more effectively – and this research is beginning to bear fruit.

For example, earlier in the year we wrote about work by Dr Janine Erler and her team, who are studying how a protein called LOX is involved in metastasis.

Adding to the story, a recent paper by Cancer Research UK-funded scientists in Oxford sheds light on how cancers spread to the brain, challenging our current understanding of how this happens.

‘Seed and soil’

Back in 1889, London doctor Stephen Paget asked “What is it that decides what organs shall suffer a case of disseminated cancer?”

The search for answers to this conundrum led to the formation of his ‘seed and soil’ concept – spreading cancer cells are like seeds from rogue weeds, spreading around a garden. But they can only root and grow if they land in suitable ‘soil’ – i.e. particular parts of the body that can support and maintain their growth.

Many cancers – including breast and lung cancer and melanoma – can sometimes spread to the brain. Once this happens, it’s often not possible to cure the disease.

The brain is a complex structure, made up of bundles of nerve fibres, blood vessels, and the connective tissue that holds it all together. Until recently, scientists had believed that cancer cells spreading to the brain tended to directly colonise nerve tissue. But until now there hasn’t been a lot of solid evidence to show this is true.

Professor Ruth Muschel and her team set out to investigate what was going on – and their findings, published in the journal PLoS One last month,  suggest that the ‘soil’ in the brain may not be nerve tissue at all, turning this received wisdom upside-down.

Hitching a lift along blood vessels

Professor Muschel and her colleagues were intrigued by anecdotal reports that secondary tumours spread along existing blood vessels within the brain– a process known as vascular co-option – rather than into nerve tissue itself.

So the team used a range of cutting-edge techniques in a mouse model system to investigate the precise order of events that happens when tumour cells spread into the brain.

By tagging cancer cells with fluorescent markers and following them under a microscope, the researchers were able to watch cancer cells forming secondary tumours along brain blood vessels.

Intriguingly, the researchers found that the cancer cells could ‘take root’ and thrive without needing to grow their own blood supply (a process known as angiogenesis, which we’ve blogged about before). This suggests that new anti-angiogenesis drugs may not be effective at halting the spread of cancer to the brain.

Taking it forward

The results challenge our understanding of how cancer spreads in the brain, but do the results from the animal studies hold up in human? To find out, the researchers looked at samples taken from patients with cancer that had spread to the brain.

They found small colonies of cancer cells growing along the blood vessels in the brain, rather than in nerve tissue, suggesting that their findings in mice closely mirror the situations in humans – an important result showing the potential of future work.

How do they stick?

Having discovered that cancer cells are attracted to blood vessels, the scientists were keen to work out how this occurred. Further lab tests revealed that a molecule called integrin beta 1, found on the surface of cancer cells, plays a vital role in allowing them to seek out blood vessels and then stick to them – a bit like molecular Velcro.

When the researchers used antibodies to prevent integrin from recognising blood vessels, or tested cancer cells that lacked integrins beta 1, they found that the cells couldn’t spread along blood vessels, and didn’t form secondary tumours. This is a fascinating finding, especially in the light of what researchers already know about integrin beta 1.

Integrin beta 1 has previously been implicated in the development of cancer, and is a good target for potential treatments. Other scientists have found that antibodies against the molecule can stop the growth of tumours grown in the lab.

Future treatments?

Although integrin antibodies are a long way from being suitable for patients, we already know that antibody treatments can be powerful weapons in our fight against cancer. For example, cancer drugs like Herceptin and Glivec are antibodies (although they are targeted to different molecules in cancer cells).

And there’s also a lot of potential to develop chemicals that could block the integrins, and stop cancer cells from sticking to blood vessels and spreading.

Although the research is still at an early stage, it could ultimately lead to new treatments for patients whose tumours have spread into their brain. And that could provide more options, longer survival, and – ultimately – hope for the many thousands of patients every year who are affected in this way.

Kat

Reference:
Carbonell, W. et al. (2009). The Vascular Basement Membrane as “Soil” in Brain Metastasis PLoS ONE, 4 (6) DOI: 10.1371/journal.pone.0005857