25 September 2014 by Clare Wilson
Magazine issue 2988. Subscribe and save
For similar stories, visit the Cancer Topic Guide Traps
and lures could stop cancer from spreading (Image: Jimmy Turrell)
Some surgery to treat cancer can actually make it spread.
But traps to mop up tumour cells as they infiltrate the body can boost chances
of survival
IT IS the medical symptom that many of us fear the most:
a lump. If it turns out to be cancer, we face, at best, a painful and
debilitating course of treatment, and at worst, well... the worst.
And yet, paradoxically, this lump is not what kills most
people. As long as it is somewhere accessible, a single, discrete tumour can
usually be cut out.
It is only once cells escape from this primary tumour and
settle elsewhere in the body – like the brain, liver, lungs or bones – that
cancer typically becomes deadly. At this stage, there may be so many secondary
tumours that repeated surgery becomes a losing battle.
This spreading process, called metastasis, is what kills
9 out of 10 people who die from cancer. "Metastasis is one of the most
important problems in the treatment of cancer," says Chris Marshall, who
studies the phenomenon at the Institute of Cancer Research in London.
Despite its importance, the way cancers spread has for a
long time remained opaque. But things are changing. New techniques to study
metastasis have led to the alarming finding that standard medical procedures to
investigate and treat cancer can sometimes help it spread.
Armed with this knowledge of how cancer disperses,
however, researchers are devising ways to trap and snare cancer cells as they
head off on this journey. As a result a whole new front is opening up in the
war on cancer.
This movie shows the migration of breast tumour cells
during metastasis deep inside the mammary tumour of a living mouse. Green
tumour cells crawl toward blood vessels (red) in response to signals from
macrophages, cells associated with blood vessels. Tumour cells then use the
blood vessels as a highway seed metastatic tumours throughout the body. One
tumour cell is 15 micrometres in diameter (Image: Evanthia Roussos and John
Condeelis/NCI)
The idea that cancer spreads from its initial site to
take root in other parts of the body was first described in 1829 by a French
gynaecologist called Joseph Récamier, who coined the term
"metastasis". Yet it has taken a remarkably long time to understand
this process. That's largely because the usual ways we investigate disease have
failed us. In people, there was no good way to monitor cells escaping from a
primary tumour and travelling around the body in real time. We can count
secondary tumours only once they are established and large enough to show up on
a scan. In mice, the go-to model for most diseases, it is rare for cancer to
metastasise naturally.
On the move
Nevertheless, slow progress has been made. Improvements
in scanning and imaging technology mean we can discern ever-smaller secondary
tumours in the human body. And by the 1990s, genetically engineered mice were
being created that were predisposed to developing tumours that spread. It is
now even possible to implant a glass porthole into the abdomen of such mice and
watch fluorescent tumour cells in motion.
From these advances, we now know that metastasis is a
remarkable process, requiring cancer cells to perform a series of distinct
feats. First they must stop dividing and acquire the ability to change shape,
enabling them to squeeze their way, like an amoeba or slug, into surrounding
tissue. If these errant cells break into a blood vessel – or lymph vessel, a
waste-collection system that drains into the blood – they will be swept into
the torrent that is our circulation. Here many tumour cells will succumb to
physical damage, or attack from patrolling immune cells. "The bloodstream
is an ugly, mean place," saysKenneth Pienta, an oncologist at the Johns
Hopkins Hospital in Baltimore, Maryland. "For a cancer cell to go through
the heart would be like us going over Niagara Falls without a barrel."
Any tumour cells that survive this ordeal must still
manage to stick to the blood vessel wall at a new site, wiggle through it into
the surrounding tissue, and start dividing once more. Put this way, it's a
wonder that any secondary tumours form at all. But only one tumour cell need
survive this journey for cancer to spread. So many researchers are now looking
for ways to intercept these marauding tumour cells.
That goal is more pressing than ever. The development of
ways to monitor levels of migrating tumour cells in the blood (see "Liquid
biopsy") has prompted a worrying discovery: some of the things we do to
diagnose and treat cancer can inadvertently send tumour cells surging into the
blood.
The suspect procedures include biopsies – in which a
small piece of the tumour is removed with a needle – and even surgery to remove
a tumour. "Surgery is a severe problem. It might produce millions of
tumour cells, increasing the risk of metastasis," says Vladimir Zharov,
who heads the Arkansas Nanomedicine Center in Little Rock.
This is such a recent finding, it is unclear exactly how
it happens, says Zharov, who was one of the first to witness such surges. In
some patients a distinct spike of tumour cells in the blood can be measured
during tumour-removal operations, so it could be that surgeons are
unintentionally cutting into the tumour. Or perhaps just cutting into a
tumour's blood supply creates suction, pulling tumour cells into the
surrounding blood vessels, he speculates (see diagram).
This will be disturbing knowledge for anyone who has to
undergo cancer surgery. Yet it is still better to cut the tumour out and risk
it spreading than to leave it alone to develop this ability by itself. And on
the positive side, says Zharov, the most promising new ways to block metastasis
might be most efficiently deployed while biopsies or surgery are in progress.
Perhaps the most obvious approach is to develop drugs
that block some molecular pathway vital to cancer cells in the process of
metastasising. One target is the crawling-around stage, one of cancer cells'
more unusual abilities.
Marshall's team is investigating a group of enzymes
called rho kinases that help pull cancer cells into the different shapes they
need to crawl through tissues. "We would really like to develop a
preventative," says Marshall. "You take a dose every day and it would
reduce the chance of metastasis."
There are other, more creative approaches in the works,
including physical traps loaded with chemicals that are irresistible to roaming
cancer cells. The nature of this chemical lure would depend on the type of
cancer. Prostate and breast tumour cells, for instance, are attracted to a
molecule called SDF-1, present in bone marrow. That is why both of these types
of cancer often spread to the skeleton, says Pienta.
His team has found that a tiny, soft sponge loaded with
SDF-1 can attract tumour cells if placed underneath the skin of mice with a
version of prostate cancer. Pienta suspects, however, that if this were done in
cancer patients, not enough cancer cells would be caught to prevent metastases.
So before they move into trials in people, his team is developing materials
that could sit right inside a blood vessel without impeding blood flow.
Other cancers may be easier to snare, though. Rather than
travelling through the bloodstream, ovarian cancer cells tend to escape into
the peritoneal cavity inside the abdomen and latch on to organs such as the
colon and bladder. So a device called M-trap has been designed to sit in the
abdomen and chemically lure in wandering cancer cells.
Although the results have yet to be published, mice with
ovarian cancer that had the trap implanted lived significantly longer than
those given no treatment, says Miguel Abal at the Santiago University Hospital
Complex in Spain, who invented the device.
In people, the idea is to implant the trap during surgery
to remove the primary tumour, and replace the trap periodically. Women with
ovarian cancer often have microscopic secondary tumours which cause the disease
to return after each surgery. Abal hopes the M-trap would mop up enough of the
metastasising cells to tip the balance in favour of long-term recovery.
Still, putting traps inside the body is an invasive
approach and some people with cancer are too weak to withstand repeated
operations. An arguably more elegant solution is to intercept roving cancer
cells without surgical intervention, using magnets, an approach being pioneered
by Zharov's team.
The first step is to make any circulating tumour cells
magnetic, by attaching cancer-specific antibodies to magnetic nanoparticles and
injecting them into the blood. The antibodies home in on tumour cells and bind
to them. Simply holding a magnet over the skin causes the cancer cells in the
blood to collect at that spot. These cells can then be killed using a laser
that penetrates the skin and heats up the nanoparticles. The heat triggers the
formation of tiny bubbles around the particles that destroy the cancer cells
(see diagram). So far, this technique has been shown to work in mice.
The big question is whether such an approach can be
scaled up to work in people. In mice, turning the laser up too high burned
their skin, but there was a middle-ground where cancer cells were killed
without damaging healthy tissue.
The technology has now been licensed to San Francisco
biotechnology firmAccurexa, which aims to run clinical trials in women having
surgery for breast cancer in about two years. The idea is to round up and kill
those tumour cells that might surge into the blood during the operation.
Just before surgery, each woman will have a magnet
attached over her palm and be injected with the nanoparticles. An hour after
the surgery is finished, any circulating tumour cells should have gathered at
the woman's palm, when they will be zapped by the laser.
Longer-term use, such as in people whose primary tumours
are inoperable, might involve wearing such a magnet permanently and receiving
nanoparticle injections and laser therapy, perhaps twice a week. Zharov doubts
that this could completely prevent secondary tumours. "But we might at
least slow the process down," he says.
Forced eviction
There is a problem, though. While these novel methods of
intercepting cancer cells as they journey from primary tumour to secondary
sites may seem promising, many people are only diagnosed with cancer once it
has already spread.
There may be ways to intervene at this stage, says
Pienta. He believes it may be possible to reverse the process of metastasis
after new tumours have formed. It's a radical idea, but work in mice suggests
that disrupting the cross-talk between cells of secondary tumours and their
environment can cause the tumour cells to be evicted and dumped back into the
blood again, where they might be dealt with more easily.
Pienta is exploring this idea with prostate and breast
cancers. Their affinity for the bone-marrow chemical SDF-1 seems to arise
because the cancer cells mimic healthy, blood-forming stem cells – whose normal
home is within our bones. By good fortune, a drug already exists that blocks
cells binding to SDF-1, which is given to people with blood cancer to flush
blood stem cells out of their bone marrow.
When mice with prostate cancer are given injections of
this drug, the cells of their secondary tumours are ejected from the bones into
the bloodstream. This raises the tantalising possibility that the same approach
could be used to help people with breast or prostate cancer that has spread to
their bones.
Pienta thinks that the shock of being ejected into the
blood might be enough to kill most of the tumour cells. But if not, giving the
patient a short blast of intense chemotherapy at the same time should finish
the job. His team aims to begin a trial in men with prostate cancer in the next
few months.
None of these techniques is likely to put a complete halt to cancer spreading, at least in their current incarnations. Yet just being able to slow or reduce the process could add years to people's lives. And it has only become possible thanks to our slow unravelling of the mysteries of metastasis, says Marshall. "It's giving us a window of opportunity."
This article appeared in print under the headline
"Fatal attraction"
Liquid biopsy
Most deaths from cancer happen after cells have escaped
from a primary tumour and set up house elsewhere in the body (see main story).
But it is only in the past decade that we have developed tools to track this
process.
A test called CellSearch allows doctors to count how many
cancer cells are in a teaspoon of blood. A reading of five or more cancer cells
suggests that the tumour is spreading.
One use of the test is to help give people a realistic
prognosis. While cancer is often portrayed as a disease that should be fought
to the death, some people choose not to spend their last months undergoing
harsh treatments if there is little hope of cure.
But counting tumour cells in the blood can also help to
keep people alive. Repeating the test over time reveals whether the primary
tumour is responding to drug therapy. If the count keeps rising, that tells
doctors they need to switch treatments.
The test has its limitations, though. At below five cells
in the sample, the accuracy suffers: some people who do have secondary tumours
score zero, because no cells end up in the sample.
Another idea is to scour the patient's entire blood
supply for cancerous cells much like kidney dialysis, in which people whose
kidneys are failing have their blood removed, filtered, and then returned.
In the case of cancer, the removed blood would be passed
through a column containing antibodies that bind to the cancer cells and trap
them as they pass. Drugs can then be tested on the extracted cancer cells, to
see which would be most effective. "It gives us the opportunity to collect
tumour cells without sticking a needle into a metastasis," says Gerhardt
Attard of the Institute of Cancer Research in London, who is part of a
consortium developing the technique.
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