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A fibroblast cell keeps its shape with actin filaments (red) and microtubules (green). Credit: Flickr/CC BY-NC-ND 2.0

In the 90s Sci-Fi dystopian blockbuster ‘The Matrix’, a computer programme shields humanity from a terrifying ‘real world’, where machines harvest energy from humans.

The system corrupts the healthy, living world around it in order to thrive.

What if we told you that there are actually a surprising number of similarities between this plotline, and the processes that can help cancer cells survive and grow within the body?

But rather than 1s and 0s, our bodies’ day-to-day support network is made up of proteins and sugar molecules that, along with supporting cells, help keep our tissues working. But this network can also be corrupted – by growing cancer cells.

Welcome, to the extracellular matrix.

At the Francis Crick Institute in London, Cancer Research UK’s Dr Erik Sahai has been studying this matrix for years, trying to understand how cancer cells can corrupt their healthy counterparts.

And today, his team – working with researchers at the University of Copenhagen – have discovered how healthy cells might help cancer cells spread to other parts of the body – and it’s all do to with the matrix and oxygen levels.

Down the rabbit hole

The discovery centres on a particular type of cell called a cancer-associated fibroblast, or CAF for short.

These are cells that tumours recruit to support them as they grow and spread. They release signals into the world around a tumour that help shape and stiffen the stringy networks of proteins and sugar molecules that cancer cells use as support when they spread.

By bending the rules of the matrix in this way, the fibroblasts can tunnel through the surrounding tissue, allowing the cancer cells to follow them down the rabbit hole to other parts of the body.

The effects are striking, as shown in this video of lab-grown cells.

Breathe Neo

For their latest study, Sahai’s team homed in on a crucial chemical balance that can affect how tumours grow: oxygen levels.

Tumours are notorious for containing pockets of low oxygen – a situation called hypoxia – and it’s been known for some time that this can trigger signals inside cancer cells that can help them survive, and even prompt the development of a new blood supply.

But how does hypoxia affect the cells and matrix that surrounds a tumour?

When the team took fibroblasts from tumours and grew them in an artificial matrix, they found that a drop in oxygen deactivated the fibroblasts.

And when the fibroblasts were exposed to low oxygen for long periods of time, and then mixed with cancer cells, these deactivated fibroblasts were no longer able to help the cancer cells move through the artificial matrix.

In other words, the fibroblasts’ ability to change the matrix and help the cancer cells spread seemed to be sensitive to changes in oxygen levels.

A glitch in the matrix?

To explore this further, Sahai’s team turned to experimental drugs known to be able to mimic the effect of hypoxia on cells.

These drugs target a group of molecules called prolyl hydroxylase domain proteins, or PHDs, which act as molecular ‘switches’ inside cells, allowing them respond to changes in oxygen levels.

When the team tested this, they found that, as predicted, the drugs softened the matrix around breast tumours in mice. And, crucially, this limited the tumour’s ability to spread.

What this shows is that prolonged hypoxia switches fibroblasts off, reducing their ability to help cancer cells spread

–  Professor Ali Tavassoli

Next, the team switched off a form of PHD – called PHD2 – inside lab-grown CAFs and mixed these with breast cancer cells. When the cancer cells formed tumours in mice, the team saw that fibroblasts lacking PHD2 were unable to help the cancer cells spread.

“This is a really interesting finding,” says Professor Ali Tavassoli, an expert in hypoxia and cancer from the University of Southampton.

“What this shows is that prolonged hypoxia switches fibroblasts off, reducing their ability to help cancer cells spread.”

And according to Tavassoli, the fact that the process only occurs with prolonged hypoxia is really important.

“The key factor is that the effects aren’t immediate, it’s a process that takes several days,” he says. “This suggests a complex and indirect set of signals may be involved, which need to be studied in more detail in further research.”

We need models. Lots of models

Sahai acknowledges that it’s still early days, but stresses that these findings suggest that PHD2 may be a promising target for drug development.

“There is already some work going on to develop drugs that target PHD2,” he says. “So these proteins can be considered a real therapeutic target.”

But the big challenge he sees in taking these results closer to the clinic is finding better ways of differentiating between affects on the tumour matrix, or the cancer cells themselves.

“In terms of what’s next, there are some big challenges,” says Sahai. “First, we don’t know enough about how well our lab models of the tumour matrix reflect the real world in patients.

“We would need to know more about this before going on to a clinical trial. As a step towards this, we are working with clinicians across London to collect CAFs from tumours removed from patients as part of their treatment so we can understand how they work.”

Ultimately, these latest findings reinforce the need to see cancer as more than just rogue cells. It’s a working ‘machine’, much like a virus, that can co-opt and corrupt healthy cells to keep growing.

For Sahai this means studying not just the tumour, but all the other tissues, cells and molecules that surround it.

By doing so, we’ll not only be able to tell you we’re working out how cancer cells spread – we may also find a way to stop them.

Nick

Reference

Madsen, C., et al. (2015). Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis EMBO reports DOI: 10.15252/embr.201540107