I want to break free – the microenvironment and metastasis

Cancer spread is a huge challenge for patients, doctors and researchers.

No man is an island, and the same can be said of tumour cells. Previous posts in our ‘microenvironment’ series have discussed how the cells and structures around a tumour – known collectively as its microenvironment – are crucial to its survival.

In this article we explore how tumours draft in these surrounding cells to break free and spread to other parts of the body.

This process of cancer spread (or metastasis) is a huge problem for cancer patients and their doctors; most deaths from cancer are caused by the disease spreading around the body. So understanding how cancer cells break free from the confines of the primary tumour and move around the body is a crucial question for scientists.

And the more we learn, the more we realise that developing the ability to spread is no easy feat for tumours – they wouldn’t get anywhere without a helping hand. So here, we’ll learn about how their healthy neighbours send them on their way.

I get by with a little help from my friends

The constant chatter between a tumour and its surroundings actively dictates its behaviour and helps it develop and flourish. And eavesdropping on this gossip has taught us that the microenvironment is crucial for helping a tumour mobilise its army of ‘mini me’s throughout the body.

The microenvironment isn’t always a bad influence; at early stages of tumour development, it can slow down a tumour’s growth – effectively giving cancer cells a molecular rap on the knuckles and telling them to play nice. But as time passes these signals are drowned out by much louder, persistent voices coaxing and goading tumour cells to hit the road.

So what changes? Almost everything. As we’ve already seen, a smouldering backdrop of inflammation causes cancer cells to gradually accumulate the genetic faults needed to cut loose from their bedfellows. And as angiogenesis takes hold and provides an escape route by way of the bloodstream, the microenvironment moves away from blocking metastasis and actively encourages the spread of cancer cells around the body.

Have stroma, will travel

The stroma – also known as ‘connective tissue’ – provides structural support to tissues and organs, but scientists are beginning to realise that it also plays a key role in tumour development. Stromal cells are co-opted to kick-start angiogenesis and inflammation, but they stick around to help cancer cells wriggle free from their neighbours and shimmy their way through the tumour mass.

They also dissolve the jelly-like superglue (called the extracellular matrix or the ECM) holding tissues together – clearing the path for tumour cells ready to escape.

Escapees next face the challenge of crossing blood vessel walls – a process called intravasation. To do this, they need chemicals called proteases, which chomp through the molecular masonry forming blood vessel walls. Although cancer cells make plenty of proteases themselves, white blood cells called macrophages also provide ample sources of the stuff – finally allowing the runaway to enter the blood vessel and set sail along the bloodstream.

We’re going to need a bigger boat

The bloodstream is a risky place for metastasising cancer cells.

The bloodstream is a particularly dangerous environment for tumour cells – it’s teeming with patrolling immune cells and the brute force of blood rushing though the circulation can be lethal.

But help is at hand. Platelets rush to the scene, lured in by chemicals produced by the flailing cell. They work by clumping together to form an insoluble mass – a particularly useful skill when a blood clot is needed following injury. But here, they form a protective shield around the tumour cell, guarding it against shearing or immune attack and helping it navigate safely through the dangerous waters.

Gimme shelter

At some point, the tumour cell arrives at a secondary site – often the lungs, brain or bone.

But the journey is far from over for this weary traveller – disorientated and far from home, tumour cells next face the challenge of setting up camp before they starve and perish.

And as you might expect, survival in this unfamiliar setting depends on making new friends very quickly – and this ‘metastatic niche’ will be the subject of our next post in this series.

No mountain high enough

For patients all over the world, the onset of metastasis is a game-changing moment in the evolution of their disease – it’s the point where the surgeon’s scalpel is no longer a cure, and successful treatment becomes extremely difficult. And each year, it’s when thousands of men, women and children are told their options have run out, and that little more can be done.

But we’re not giving up. Even a casual glance through human history shows our endless capacity to tackle seemingly insurmountable physical and intellectual challenges – we’ve survived the ice age, we’ve split the atom and we’ve been to the moon and back. For cancer researchers and patients, metastasis is possibly our biggest challenge.

But thanks to a little help from our friends – and the ingenuity of our scientists up and down the country, we will get there.

Further reading
Joyce J.A. & Pollard J.W. (2008). Microenvironmental regulation of metastasis, Nature Reviews Cancer, 9 (4) 239-252. DOI: 10.1038/nrc2618