Melanoma Cells: A Fatal Attraction to LPA
A hot day, blue sky and an even bluer sea. A perfect day to spend on the beach. But while our skin is sizzling, very few of us are aware of what some of our cells might be up to. Melanoma cells could be busy dividing and trying to escape the skin in search of a blood vessel through which to colonize other parts of our body. But how do they decide it’s time to migrate from the skin? Is there some sort of “go” signal that makes them leave their safe haven and cause havoc elsewhere?
Andrew Muinonen-Martin and researchers from the Beatson Institute at the University of Glasgow led by Robert Insall have been busy trying to find a way to stop this aggressive cancer spreading. In a new article just published in PLOS Biology, they tell us about a very promising breakthrough in their search for this “go” signal that could be disrupted to prevent metastasis of these tumors.
Why should we worry if we suddenly realize that we have a strange mole growing in our skin at an alarming pace? Melanocytes (a specialised skin cell) produce a pigment called melanin whenever we are exposed to sunlight – this is what gives us the highly desired tanned look. However these melanocytes aren’t born in the skin, but in a far-away developmental tissue called the neural crest; their long migration to the skin where they can protect us against UV light means that they’re naturally good ‘runners’.
As we well know, these guardians of our skin can occasionally turn nasty – when a dangerous mutation occurs that transform them in cancer cells, they start proliferating horizontally within the skin. This would be unpleasant if it remained confined to the skin, but then something happens that make these cells to migrate downwards instead until they manage to escape into the body. This is the dreaded phase of melanoma: within weeks these highly mobile cancer cells can spread all around the body, with disastrous and often lethal consequences.
Insall, Muinonen-Martin and colleagues focus their research on chemotaxis – chemical cues that attract and direct cells’ movements – and they set up to try to identify a potential signal that might be triggering the melanoma cells’ deadly migration. They tested the effect of several known chemoattractants by closely watching the migration of melanoma cells in direct-viewing chambers that they previously developed. They found that lysophosphatidic acid (LPA), a fatty chemical common in human tissues – and in the serum used in cell culture medium – was able to attract these cells particularly efficiently. But in order to attract cells, a chemoattractant needs to be present in the form of a gradient so that cells can move from a region with less of the chemical to areas where it is more abundant. How is a potential LPA gradient formed in these tumors?
Watch this video of melanoma cells swarming from an area of low LPA – on the left – to an area of high LPA – on the right (credit: doi:10.1371/journal.pbio.1001966):
The team analyzed the culture medium from groups of melanoma cells with different densities and saw that the cells were effectively breaking down the LPA molecules nearest to them. The result is a self-generated LPA gradient; low where cells have grown a lot – for example a tumour – and high away from the tumour where there are no melanoma cells. The researchers then looked closely at the more realistic ‘in vivo’ scenario in real tumours from mutant mice that are susceptible to melanoma. They took biopsies from different areas around the tumour, and use mass spectrometry to measure LPA levels. Again, this revealed an outward gradient. Cells located close to the center of the tumour were exposed to low levels of LPA, whereas cells at the edges of the tumour had access to much higher levels. Inevitably, this gradient seems to attract melanoma cells out of the tumour, following the scent of LPA and blazing a trail outwards, perhaps to a handy blood vessel.
The conclusion is, therefore, that the melanoma generates the signal for its own metastasis. But the researchers’ identification of the bearer of this signal leaves a door open for hope. If we can manage to stop LPA gradients being generated in the tumor –perhaps by inhibiting the enzyme that breaks LPA down – metastasis of these cells might become preventable. In the meanwhile, while a ray of hope shines in the sky, make sure you and your skin stay well protected with sunscreen.
Muinonen-Martin, A., Susanto, O., Zhang, Q., Smethurst, E., Faller, W., Veltman, D., Kalna, G., Lindsay, C., Bennett, D., Sansom, O., Herd, R., Jones, R., Machesky, L., Wakelam, M., Knecht, D., & Insall, R. (2014). Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal PLoS Biology, 12 (10) DOI: 10.1371/journal.pbio.1001966