How cancer was created by evolution

bbc.com/earth/story/20160601-is-cancer-inevitable

By Melissa Hogenboom 2 June 2016

Will we ever win the "war on cancer"?

The latest figures show just how distant a prospect victory is right now. In the US, the lifetime risk of developing
cancer is 42% in men and 38% in women, according to the American Cancer Society. The figures are even worse in
the UK. According to Cancer Research UK, 54% of men and 48% of women will get cancer at some point in their
lives.

And cases are on the rise. As of 2015 there are 2.5 million people in the UK living with the disease, according to
Macmillan Cancer Support. This is an increase of 3% each year, or 400,000 extra cases in five years.

Cancer is not only extremely pervasive, but also becoming more and more common

Figures like this show that cancer is not only extremely pervasive, but also becoming more and more common. But
why will so many people develop the disease at some point in their lives?

To get to the answer, we must understand that cancer is an unfortunate by-product of the way evolution works.
Large and complicated animals like humans are vulnerable to cancer precisely because they are large and
complicated.

But even though it is evolutionary processes that have made cancer such a problem, it is also evolutionary thinking
that is now leading to pioneering treatments that could stack the odds against cancer and in favour of our health.

The better a cell is at dividing, the more successful it will be (Credit: Sebastian Kaulitzki/Alamy)

To understand how cancer exists at all, we need to go back to a fundamental process that occurs in our bodies: cell
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division.

A cancerous cell breaks all the rules of controlled division that our other cells follow

We each started out when an egg and sperm cell met and fused. Within a few days, that egg and sperm had turned
into a ball containing a few hundred cells. By the time we reach adulthood about 18 years later, those cells have
divided so many more times that scientists cannot agree, even to the nearest few trillion, exactly how many cells our
bodies contain.

Cell division in our bodies is very heavily controlled. For instance, when you were first growing your hands, some
cells went through "cell suicide" a process called apoptosis to carve out the spaces between your fingers.

Cancer is also all about cell division, but with one important difference. A cancerous cell breaks all the rules of
controlled division that our other cells follow.

"It is like they are a different organism," says developmental biologist Timothy Weil of the University of Cambridge in
the UK. "The better that cell gets at dividing faster than its neighbours and gaining nutrients, the more successful it
will be as a cancer, and the more likely it will survive and grow."

Healthy cell division is marked by control and restraint, but cancerous cell division is wild, uncontrolled proliferation.

"Adult cells are constantly under strict control," Weil says. "Basically cancer is a loss of control of those cells."

Cancer cells can quickly grow out of control (Credit: Nobeastsofierce Science/Alamy)

Cancer can only grow in this uncontrolled fashion if some of the genes that usually stop any accidental cell growth
such as the p53 gene get mutated in the cancer cells.

If just a few survive they have the potential to rapidly multiply again and regrow the tumour

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However, our bodies are pretty good at spotting these mutations. There are biological systems within us that step in
to destroy most mutated cells before they can cause us harm.

We have several "corrective" genes which send instructions to kill any corrupted cells. "There's millions of years of
evolution that's gone into this," says Charles Swanton of the Francis Crick Institute in the UK. "It's pretty good but it's
not quite perfect."

The threat comes from the tiny number of corrupt cells that do not get fixed. Over time, one of these cells can grow
and divide into thousands, then tens of thousands of cancer cells. Eventually there may even be billions of cells in a
tumour.

This leads to a truly challenging problem. Once that initial corrupt cell has divided and multiplied into a tumour, a
person will have cancer until every single one of the cancer cells has been obliterated. If just a few survive, they can
rapidly multiply and regrow the tumour.

As cancer cells mutate, they continue to increase in genetic diversity (Credit: Mopic/Alamy)

Cancer cells are not all alike: far from it. Whenever a cancerous cell divides, it has the potential to pick up new
mutations that affect its behaviour. In other words, they evolve.

No two cancer cells in a tumour are the same

As the cells inside a tumour mutate, they become ever more genetically diverse. Then evolution goes to work to find
the most cancerous ones.

Genetic diversity is "the spice of life, it's the substrate upon which natural selection acts", says Swanton. By this he
means evolution by natural selection, first proposed by Charles Darwin in 1859.

Just like individual species humans, lions, frogs, even bacteria gain genetic variation over time, so too do cancer
cells. "Tumours don't evolve in a linear manner," says Swanton. "They evolve in a branched evolutionary manner,
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which means that no two cells in a tumour are the same."

In effect, the cells of a tumour are evolving to become more cancerous. "Essentially we are dealing with branches of
evolution that create diversity and that create fitness, and allow cell populations to survive therapy and ultimately
outwit the clinician," says Swanton.

A cancer tumour is like a tree with many branches where each new branch has new mutations (John Shortland/CC
by 2.0)

The fact that tumours are constantly changing their genetic makeup is one of the reasons why cancers are so hard
to "kill".

It is for this reason that Swanton, and others in the field, take an evolutionary approach to tackling cancer. Swanton,
who specialises in lung cancer, is both a clinician and a research scientist. His work has revealed something that he
hopes will help create effective, targeted treatment.

Think of the evolution that goes on inside a cancer tumour as like a tree with many branches

Think of the evolution that goes on inside a cancer tumour as like a tree with many branches. At the base of the tree
are the original mutations that triggered the tumour in the first place: mutations that should be shared by all of the
cancer cells in the tumour.

In theory, a therapy that targets one of those base mutations should destroy every cell in the tumour. This is an
approach that some therapies already use. For instance a drug called EGFR therapy targets lung cancer, and
a BRAF inhibitor protein attacks the faulty gene which can lead to melanoma.

The trouble is, these therapies do not work as well as we might hope. Even in these targeted therapies, resistance
often appears over time.

"It occurs because there will be one or more cells in the tumour branches that has a resistance mutation that allows
it to outwit the therapy," Swanton says.
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In other words, some of the branches of the cancer tree have evolved in a way that makes them less vulnerable to
attack through the base mutation. They can dodge the therapy.

Cancerous cells often need to be attacked more than once (Credit: JC Revy/ISM/SPL)

Swanton and his colleagues have studied the problem to see if they can develop a therapy with a better outcome .

An average tumour might contain something like a thousand billion cancer cells. Some of those cells might well
have evolved in a way that makes them immune to attack through a specific basal mutation.

Targeting three base mutations at the same time will "chop the trunk down" and destroy every single
cell in the tumour

But what if a therapy targeted two of those basal mutations at the same time? Far fewer cells will have evolved in a
way that makes them immune to both forms of attack.

Swanton and his colleagues crunched the numbers to see how many base mutations in the cancer "trunk" they
would have to target simultaneously to ensure that they could successfully destroy every one of the cancer cells.
Three was the magic number. Their calculations suggest that targeting three base mutations at the same time will
"chop the trunk down" and destroy every single cell in the tumour.

However, this approach is not going to be cheap. To work, it requires the researchers to study a person's specific
cancer to establish which base mutations their tumour has, so that the right cocktail of therapies can be applied.

"What we've come up with is an approach where we sequence tumours and produce the truncal antigens on a
patient-by-patient basis," Swanton explains.

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 Sun exposure can cause DNA damage (Credit: A.P.S. (UK)/Alamy)

Colorectal cancer researcher Alberto Bardelli of the University of Turin in Italy, has also been using evolutionary
theory as inspiration for a potential solution to overcoming drug resistance.

"I was very disappointed by the fact that all tumours became resistant," he says of his previous work. Now Bardelli
has used the reality of drug resistance to develop a new anti-cancer therapy.

He begins by teasing out the resistant cancerous cells, which he calls "clones". Patients are given a particular drug
therapy and then monitored to see when a particular cancerous "clone" rises to dominance in the tumour because it
has developed drug resistance.

We use the tumour against itself it's a war of cancer clones

Then Bardelli stops treating the cancer with the drug. This removes the evolutionary pressure that allowed the clone
to become so successful. Without that pressure, other types of cancer cell in the tumour also have a chance to
flourish. They "fight back" against the dominant clone. In effect, the cancer effectively begins to war with itself.

When some of those other clones have gained ground, it is time to administer the drugs again, as these new clones
should not yet have developed resistance. Bardelli calls it "the war of clones".

"We use clones against clones, we wait for the winners, then take out the pressure; the drug. The winners at this
point are unfit and start to disappear, and then others take over. So we use the tumour against itself.

"I want to use the portion of the cells that are not affected by the therapy to fight back the others."

For now we do not know if this tactic will work or not. His team is starting a clinical trial in the summer of 2016.

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 Targeted drugs can cause some cancer cells to dissolve (Credit: Alfred Pasieka/SPL)

These evolutionary approaches may show great promise, but at the same time it is important to better understand
the many triggers that can cause cancer in the first place.

In 2013 one of the biggest genetic studies took an important step forward in doing so. Researchers scoured cancer
patients' genomes to look at "signatures" of the 30 most common cancer mutations.

It is important to better understand the many triggers that can cause cancer in the first place

These signatures represent small chemical changes to the DNA in cancers including lung, skin and ovarian
cancer. Andrew Biankin, a surgeon at the University of Glasgow in the UK, was one of the researchers involved. He
says it was possible to observe the "insult to the DNA" that left a tell-tale sign of the damage.

"In skin cancer like melanoma, we can see evidence of UV light exposure, in lung cancer can see a particular
signature of smoking exposure," explains Biankin. "We can see evidence of there being an inherited inability to
repair DNA."

As well as these known cancer signatures, the team could see unusual cancer-forming patterns where the cause
was unclear. "There's [now] a lot of effort in trying to work out what these causes are," he says.

The core challenge for researchers like Biankin and Cancer Research UK, who funded the study, will be to
understand exactly what leads to these types of genetic change.

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 Many cancers leave clear marks on our DNA (Credit: Paul Wootton/SPL)

While it is vital to understand the causes of cancer and to find new treatments, others stress that for now it is more
important to focus on prevention. That is because there are known risk factors that contribute to cancer-causing
mutations, such as smoking and sunburn.

Otis Brawley, chief medical officer at the American Cancer Society, says focusing on some of these risks could
prevent many instances of cancer forming in the first place. He cites two startling statistics: in 1900 the age-adjusted
death rate for cancer in the US was 65 per 100,000, but this had jumped to 210 deaths per 100,000 only 90 years
later.

Tobacco is the single most preventable cause of death in the world

"If you have something that has increased that quickly over 90 years, there's something that causing it," says
Brawley. "If you can remove the cause you can decrease the cancer."

In the US there has been a 25% decline in death rate in the last two decades. "More than half of that decline is
driven by cancer prevention activities," says Brawley.

This points to the fact that some of the cancers that would previously have killed people had been prevented. Almost
a third of death from cancer in the US has been attributed to cigarette smoking, for example. This makes tobacco
"the single most preventable cause of death in the world", according to Cancer Research UK.

Although it is obviously good that death rates are falling, overall cancer diagnoses are on the rise.

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 Smoking is a leading cause for cancer (Credit: DBURKE/Alamy)

There is a degree to which this is because certain cancers are now better diagnosed, and so cases are more likely
to be identified and counted. This is true of prostate cancer, for instance.

But a more telling reason for the rise is that humans, on average, live a lot longer than they used to. "If you live long
enough you will get cancer," says Biankin.

"If we decide that we all want to live to more than 70, then we have to accept that sooner or later we will get some
sort of cancer," says Bardelli. It is inevitable because our cells have not evolved to maintain their DNA for as long as
we now live, he says.

If we decide that we all want to live to more than 70 then we have to accept that sooner or later we
will get some sort of cancer

Brawley goes even further, and says that everyone over 40 will get a mutation that can cause cancer at some point.
That sounds alarming, but fortunately our natural defence mechanisms will usually stop the mutation in its tracks by
destroying the mutant cell before it can grow into a full-blown tumour.

Even though the rise in cancer is an almost inevitable consequence of other improvements in our health, progress
towards better treatments is continuing apace.

And peering back into how life works to "fight evolution with evolution" may well provide further breakthroughs. "Our
host, our body has to make use of resources that have been growing for millions and millions of years," says
Bardelli.

"There is hope. I have no doubt we will beat cancer, no doubt," he says. "Sometimes we fail because we don't
identify the problem as it should be. It's nobody's fault, it's how science works."

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