Antioxidants, free radicals and melanoma spread – what’s going on?

In recent years, a multi-billion pound global industry has sprung up selling antioxidant supplements.

Various pills and potions are heavily promoted as being ‘good for us’ – allegedly by mopping up chemicals in our bodies called free radicals.

These supposed baddies are created, in the main, through the chemical reactions necessary to life within our cells.

This idea that they’re harmful is based on evidence from lab experiments showing that free radicals can damage our DNA, theoretically leading to the genetic chaos that drives cancer. So – in theory at least – adding more antioxidants into the body could have a protective effect.

But as we’ve explored in previous articles, there’s actually very little solid evidence that antioxidants reduce a person’s risk of cancer, nor help treat the disease. In fact, some large clinical trials even show the opposite.

So are free radicals really as villainous as they are portrayed to be? And what role, if any, do they play in driving the growth and spread of cancer after it’s developed?

Understanding how free radicals behave in cancer cells – and how antioxidants affect them – could ultimately lead to improvements in the way cancer is treated – but the picture at the moment is far from clear.

An intriguing Cancer Research UK-funded study, led by Dr Victoria Sanz-Moreno and published in the Journal of the National Cancer Institute, has begun to add some clarity to this mystery, and adds to growing evidence that free radicals may not be so bad after all.

And, taken together with recent results from a Swedish study in mice showing that antioxidants can make melanoma more aggressive, it provides growing evidence that these supplements play a more complicated role than previously thought.

It’s only Rac ‘n Rho

Dr Sanz-Moreno studies how melanoma, the most serious form of skin cancer, spreads around the body (or metastasises) – making it a lot harder to treat.

Back in 2008, as part of a Cancer Research UK-funded team at the Institute of Cancer Research, Sanz-Moreno discovered that the likelihood of melanoma cells spreading is affected partly by their shape. And we now know that their shape is determined, in part, by the levels of two key molecules – Rac and Rho.

“Higher levels of Rac activity, along with low Rho levels, makes cells take a long, spindly shaped form. These cells act like they’re covered in Velcro – they stick to their neighbours and can’t move about as much,” Dr Sanz-Moreno tells us.

An elongated melanoma cell in red. Credit: Dr Victoria Sanz-Moreno

“In contrast, if Rho is calling the shots and there isn’t much Rac, the cells rearrange their internal scaffolding and round up, becoming less sticky and travelling more freely.”

And last year, Sanz-Moreno’s team – now based at King’s College London – discovered that it’s these rounded, mobile cells that pose the biggest danger of skin cancer spreading.

Shifting shapes

Although free radicals are usually seen as damaging, they can also do useful things in the body. Immune cells use them to destroy bacteria, they relax blood vessels to lower blood pressure, and they’re instrumental in giving cells critical information about their environment and whether their metabolism is too high or low.

And it turns out that one of the roles Rac plays is to increase the levels of free radicals in cells.

Dr Sanz-Moreno and her team have spent the last few years investigating whether free radical levels in lab-grown melanoma cells are affected by levels of Rac and Rho – and, crucially, whether this helps or hinders their capability to spread.

First, they treated the cells with powerful antioxidants, which mop up all the free radicals. The cells became more rounded – the more dangerous shape that’s more likely to spread.

Conversely, if the cancer cells were treated with experimental drugs that boost Rac signalling, the opposite happened. Free radical levels increased, and the cells became long and spindly, losing their ability to move around as much.

Round melanoma cell in red. Credit: Dr Victoria Sanz-Moreno

When the researchers dug down into what was happening on the genetic level, they discovered what was going on. The increase in free radicals was switching on genes that helped repair damaged DNA, including an important molecule called PIG3, which helps orchestrate the DNA repair machinery.

In turn, they discovered that this boost in PIG3 and DNA repair led to higher levels of one of the most important molecules that protect us against cancer, known as p53.

Further studies added more weight to these findings: mice with skin tumours were more likely to survive if their cancer cells had higher levels of PIG3, p53 and free radicals. And this turned out to be because their tumours grew more slowly and didn’t spread as much.

To find out if this held true in patients with the disease, they tracked down two more pieces of the jigsaw puzzle.

Firstly, they turned to a publicly-available database known as The Cancer Genome Atlas, which holds DNA and molecular information from thousands of patients with different types of cancer. They revealed that melanoma samples in the database which had come from patients whose cancers had spread also had low, or no PIG3, and indications that Rho was highly active.

Then they analysed more than 160 samples from patients with melanoma. In line with all their previous observations, 8 out of ten samples had low or absent PIG3, and these cells were much more likely to look dangerously rounded.

What does this mean for treatments?

Most of Dr Sanz-Moreno’s work was carried out in lab-grown skin cancer cells, so there’s still more work to be done to show whether the experimental drugs they used would be effective in melanoma patients.

But these drugs are being tested in clinical trials for other diseases – such as the eye condition glaucoma, high blood pressure, strokes and heart disease – so doctors already know they are safe for people to take, paving the way for trials with cancer patients.

Dr Sanz-Moreno’s findings also help explain the unexpected results from mouse studies and clinical trials testing antioxidants as a cancer preventative. Several trials surprisingly showed that high doses of antioxidants could in fact increase the risk from lung and prostate cancer – one of these trials showed such a negative effect it had to be stopped early, so as not to put people at higher risk.

What’s more, some cancer treatments, like radiotherapy and chemotherapy, actually depend on free radicals attacking DNA to destroy cancer cells. High-dose antioxidants could make these treatments less effective.

And Dr Sanz-Moreno’s findings fit with the recent work of two other teams (one based in Sweden and one in the US), who have both shown that higher levels of antioxidants seem to encourage skin cancer cells to spread.

So where does this leave antioxidant supplements, given that they seem to encourage cancer cells to go on the move?

“While our results don’t prove that antioxidants are harmful for healthy cells, they highlight an important note of caution about giving antioxidants to people that already have cancer,” Sanz-Moreno says.

In other words, while most of the evidence comes from experiments with animals, it’s painting an increasingly complicated picture – far more complex than the simple ‘antioxidants = good’ equation you might be led to believe from a lot of the information you might read online.

If you have been diagnosed with cancer, we strongly advise talking to your doctor before taking any nutritional supplements, especially as it’s far from clear whether they’re as good for you as their manufacturers would have you believe.

Emma

• A version of this post also appeared on The Conversation website