Most of the deaths caused by cancer happen after cells break away from the initial tumour and spread to other sites in the body – a process called metastasis.
But surviving in a foreign region of the body isn’t easy, even for cancer cells. It’s a bit like having to move house – you have to uproot yourself, breaking any connections you had with your former home and make it through moving day, dealing with packing your possessions and other challenges that present themselves, and finally settling down in your new home.
Much like moving house, metastasis doesn’t occur at random. It’s a controlled and deliberate process and, crucially, one that could be interrupted, if only we can fully understand it. So researchers around the world are desperately trying to gain insights into how and why cells travel around our bodies – both in the development of cancer, and under ‘normal’ circumstances when cells are expected to move, such as when humans develop in the womb from an embryo into a beautiful, bouncing baby.
In June, researchers at University College London made a fascinating finding in frog and fish embryos. They elegantly showed that, as the embryo develops to form the body of the baby animal, its cells seem to play a game of ‘chase’ to get into the correct location. Some media outlets breathlessly reported that scientists had “uncovered what causes cancer to spread”, which is a little far-fetched based on the actual research – as we’ll see.
So what does this study really add to our understanding of cancer cells? Does it reveal new hints as to how they move around the body? And where does it fit into the wider context of what’s known about metastasis? And, perhaps more fundamentally, how can studying the movement of cells in embryos help researchers understand metastasis?
Embryos and cancer
Animals like mammals start life as a single fertilised egg cell, which has to divide over and over again to make enough cells to sculpt the baby animal. And these cells have to organise themselves to create all the different specialised types of cells that make up the animal’s body – skin, hair, gut, blood, brain – the whole lot.
But while they’re becoming specialised, the cells in an embryo also have to move around to get into the right place, so that everything is where it should be, with a brain at the front, guts in the middle and so on. These processes of cells dividing, specialising and relocating are subverted in cancer, where cells grow out of control, forget what they’re meant to be doing, and start spreading around the body.
In fact, since all of the cells in our body contain the same ‘recipe book’ – the genetic instructions encoded within our DNA – they all contain the basic instructions to divide, develop and disperse. Researchers now know that as they grow and spread, cancer cells ‘reawaken’ many processes that once occurred in the embryo, using many of the same genes and mechanisms.
So studying how cells divide and move around in embryos may provide insight into what’s happening in cancer.
Follow the van
The UCL researchers were studying the development of frog and fish embryos. In particular, they were looking at the way two types of cell interact during this process: placodal cells, which go on to become part of the animals’ sensory organs, and neural crest cells, which ultimately give rise to skin pigment cells called melanocytes.
Through a series of experiments detailed in their paper in the journal Nature Cell Biology, the researchers showed that, as placodal cells moved around the developing embryo, they were relentlessly chased by neural crest cells. To use our house-moving analogy, the neural crest cells are a bit like people desperately following the removal van to get to their new home on moving day.
The researchers also found that this cellular chase happens because placodal cells (the removal van in our analogy) secrete a chemical called SDF1 that the neural crest cells simply can’t resist. But as soon as the neural crest cells catch the placodal cells, these very quickly run away from the neural crest cells again. Much like if our hapless homeowners were to catch up with their removal van at traffic lights, only to have to chase it again as it speeds off when the lights go green.
You can watch some videos of the cells playing chase in the third row down here.
The authors called the behaviour they observed in the embryos ‘chase-and-run’. And crucially, the behaviour was co-ordinated by the cells themselves, just by interacting with each other. This is a significant and fascinating discovery from a developmental biologist’s point of view – but how does it relate to cancer?
For a start, not all of the cell types used in the study are directly relevant to cancer. Placodal cells, for example, are a type of cell known as an ‘epithelial’ cell. These make up your outer skin layer and line internal organs such as the gut. They generally don’t move around in adults, so studying how they move in an embryo may not reveal much about cancer spread.
However, the neural crest cells are much more important, because they form melanocytes. These are the cells that go rogue in malignant melanoma – the most dangerous form of skin cancer which is notorious for spreading aggressively.
So far, the researchers have only shown that this “chase and run” phenomenon may take place during development in the womb, so more work needs to be done to find out if it does play a role in metastasis. But if it does, there are big implications.
Professor Robert Insall, an expert in cancer cell movement based at our Beatson Research Institute in Glasgow, told us it was an “exciting and important” development, because it suggests that cancer cells themselves might govern where and how they spread, rather than being ‘summoned’ by other body parts. “In cancer it may be that there’s no ‘malign force’ directing movement of the cancer cells to other organs. It may all be organised by the cells themselves, from within,” he said.
So finding out if this happens in cancer could be an important step in developing a full understanding of metastasis, to bring us closer to stopping it.
What do we know about how cancer cells spread?
This research is part of a bigger picture emerging from labs around the world –including those funded by Cancer Research UK – and we’ve previously written about some of their work.
For example, our researchers in Glasgow found that a gene called Rac1 is involved in immature skin pigment cells moving around, one of the first steps in the development of melanoma. Another group of our scientists found that cancer cells are shape-shifters, changing their shape so they can wriggle through the tight spaces between other cells and escape into foreign territory.
And scientists at our London Research Institute have shown that non-cancerous cells called fibroblasts spread around the body along with cancer cells. In fact, it looks like the fibroblast cells actually lead the invasion, punching holes in surrounding tissues so the tumour cells can follow in their tracks.
It’s possible that some or all of these different mechanisms play a role in how cancer spreads – so we urgently need to find out how this complex puzzle fits together. If this new study is indeed a window into how cancers spread, then could SDF1, the chemical that attracts neural crest cells, form a new target for treatments that make the cancer cells stay put, rather than going on the move?
This new study adds a vital piece to the puzzle, taking us a step closer to fully understanding metastasis. But there’s a long way to go before we fully comprehend this complex and fatal process.
Theveneau E et al. (2013). Chase-and-run between adjacent cell populations promotes directional collective migration, Nature Cell Biology, 15 (7) 763-772. DOI: 10.1038/ncb2772