Tracking melanoma’s deadly path

Source: Cosmos, by  James Urquhart, October 2014

Scientists have worked out the mechanics of how melanoma spreads to the bloodstream. Their findings may lead to more effective treatments.

One day it’s a dark mole on your skin, the next it’s a life-threatening melanoma rampaging through your bloodstream. But how do the cancer cells find their way to the blood vessels in the first place? By following a chemical gradient, say a team of scientists reporting in the journal PLOS Biology.

Around 132,000 new melanoma cases are diagnosed each year, close to 10% of them in Australia – the country with the world’s highest incidence thanks to the mass exposure of fair European skin to the Sun’s UV rays. As a small skin mole a melanoma is curable, but once it spreads through the bloodstream it’s almost impossible to treat.

Now, Andrew Muinonen-Martin and Robert Insall at Cancer Research UK Beatson Institute in Glasgow, and their colleagues in the UK and US, have spied melanoma cells from patients and in mice tracking their way to the bloodstream by following the trail of a chemical called lysophosphatidic acid (LPA).

LPA is found within cells and tissues and also in the bloodstream, where it triggers cell division. Cancer cells have been found to develop an unhealthy appetite for LPA which in turn fuels their uncontrolled growth. In the case of melanoma cells it appears that the thirst for LPA also drives them towards the blood vessels.

Once melanoma cells are in the bloodstream they can
quickly travel anywhere in the body.

When a tumour is small, enough LPA diffuses in from surrounding tissues to satisfy it. “The biggest surprise was that the melanoma cells rapidly break down the LPA they’re responding to,” says Insall. That means the levels of LPA plummet in the vicinity of the tumour. So, as the tumour grows, some of its cells break away and start to migrate in search of more LPA. Since LPA is mainly produced by blood platelets the melanoma cells follow the LPA concentration gradient into the bloodstream, says Insall.

The researchers filmed the LPA-starved cells and found they move a millimetre a day, which is extremely fast for cancer cells. At this pace, moving from the tumour to the bloodstream takes a matter of weeks. Once melanoma cells are in the bloodstream they can quickly travel anywhere in the body.

Although it was already known that melanoma cells move in response to chemical cues it was not known that LPA provided the pathway, says Kimberley Beaumont who investigates melanoma biology at the Centenary Institute in Sydney.

“The gradient of LPA is produced by the tumour itself once it reaches a certain size – demonstrating how melanoma is able to manipulate its environment to enable disease progression,” she says.

The newfound knowledge could help guide doctors on how to treat the disease.

“If we could use the presence or absence of an LPA gradient to tell whether a melanoma was spreading or not, we could give fewer people chemo,” Insall explains.

Knowing the tracks that are used also has researchers thinking about how to disrupt them. Insall suspects other cancers may also spread this way.

  “I think self-generated gradients will be huge, possibly using different chemical signals. We will be looking for something that we hadn’t dreamed was there,” he says