This entry is part 5 of 5 in the series Microenvironment
In our previous post in this series, we talked about how the tumour microenvironment helps tumour cells leave a primary tumour and set sail along the bloodstream.
The vast majority of these drifting cells eventually arrive at a secondary organ where they need to settle and establish themselves – or die.
But settling in a secondary organ presents a huge challenge for cancer cells – and it’s one they can’t overcome without help from ‘friendly’ locals.
Here, we’ll see how the primary tumour and the secondary organ conspire to create the ‘metastatic niche’ – a welcoming and fertile microenvironment where tumour cells can settle, grow and colonise.
The discerning traveller
Doctors have known for a long time that tumours tend to spread to specific organs. For example breast cancers often spread to the lungs, liver and brain while prostate cancers usually head for the liver and the bone.
But what makes tumours so picky?
Back in 1889, most doctors believed that secondary sites were chosen at random and cancer cells merely set up camp wherever they happened to wash up. But this theory didn’t quite sit right with a young British surgeon by the name of Stephen Paget. So he did what any self-respecting scientist would do – he did some research.
Paget looked at the detailed autopsy records of more than 700 patients with breast cancer that had spread. He noticed that breast tumours spread to the liver more than any other organ in the body – something that couldn’t be explained by blood flow – because the spleen (an organ neighbouring the liver with a similar blood flow) – almost never saw metastases.
Paget wrote his ideas up in a paper proposing that ‘the seed’ (a metastasising tumour cell) could only grow in suitable ‘soil’. Or in other words: there was nothing random about the choice of secondary organ at all – some organs were simply more hospitable than others.
So what makes these particular organs so special? The short answer is that we don’t really know – but research in this area has unearthed some fascinating findings.
Finding the local hotspots
Incredibly, some research suggests that growing tumours send chemical messages to the lung – a common site of metastasis – effectively ‘phoning ahead’ to ensure that preparations for the arrival of the first tumour cells are in place. The researchers also found that lungs responded – with the help of cells called myeloid cells – by kick-starting inflammation which wandering tumour cells find irresistible.
These early changes in secondary organs which occur before tumour cells arrive create what scientists call the ‘pre-metastatic niche’ – a relatively new concept in biology. It’s a far cry from the random model of metastasis that Paget challenged because it’s based on the idea that the primary tumour controls where its seedlings go.
But what happens when the pre-metastatic niche opens for business?
Rooms available – the metastatic niche
When the first tumour cells arrive, the pre-metastatic niche becomes the metastatic niche and its role in determining tumour cell fate becomes more crucial than ever before.
Researchers also think myeloid cells help protect tumour cells from patrolling immune cells. We don’t completely understand how they do this, but there’s some evidence that they produce molecules which dampen the immune system – allowing tumour cells to rest and recuperate undetected.
In other words, when tumour cells arrive, secondary organs work hard to keep them there and keep them safe.
Chatting to the locals
But docking safely to the target organ is the easy bit – the real challenge is learning to adapt and thrive in a foreign environment. Yet again, success depends on productive interactions with the local community.
For starters, tumour cells have to quash the urge to self-destruct that usually comes with being alone in a foreign land. But again, welcome signals from its new environment are thought to help soothe and reassure.
Local tissue is also a handy source of ‘growth factors’ – molecules that cells depend on to grow and thrive. These are invaluable as tumour cells get to work on the crucial task of building their own blood supply and forming colonies of their own.
Making the hospitable inhospitable
Research is always a voyage into the unknown and the best studies often throw up more questions than answers.
We’ve still got big questions to address. We need to understand how target organs are chosen by tumours, and we’ve got to decipher the molecular chatter between the primary tumour and the target organ in different cancer types.
So we’ve got a long way to go but dissecting the role of the microenvironment should fill large holes in our understanding of this complex and deadly process.
And the potential rewards are significant. In the future, we might even be able to make secondary organs ‘deport’ tumour cells – stopping metastasis before it even has a chance to take hold. Given that around nine in ten deaths from cancer are caused by metastasis, this approach could save thousands of lives in the future.
Stephen Paget died in 1926 at the age of 71. At the time of his death, the scientific community had yet to fully embrace his ideas but today, he’s rightfully recognised as a pioneer and the father of one of the ‘hottest topics’ in cancer biology. It’s just a shame that he didn’t live to see his landmark ‘soil and seed’ theory bear fruit.
Psaila, B., & Lyden, D. (2009). The metastatic niche: adapting the foreign soil Nature Reviews Cancer, 9 (4), 285-293 DOI: 10.1038/nrc2621