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Selfish Shellfish Cells Cause Contagious Clam Cancer

In the 1970s, scientists noticed that soft-shell clams along the east coast of North America were dying from a strange type of cancer. Their blood, which was typically clear, would fill with so many cells that it would turn milky. The rogue cells clogged and infiltrated the clams’ organs, often killing them.

This cancer—this clam leukaemia—seemed to be transmissible. If you took the blood of infected clams and injected it into healthy individuals, some of those recipients would develop the disease. For years, scientists suspected that a virus was involved

Michael Metzger from Columbia University has a different explanation. His team has discovered that the thing that transmits the cancer isn’t a virus, but the cancer itself.

The clam leukaemia is a contagious cancer—an immortal line of selfish shellfish cells that originated in a single individual and somehow gained the ability to survive and multiply in fresh hosts.

The vast majority of cancers are not like this; they’re not contagious. Some are caused by contagious things, like viruses (HPV causes cervical cancer) or bacteria (Helicobacter pylori causes stomach cancer), but the cells themselves cannot leave one host and start growing in another. Once their host dies, so do they.

Until Metzger’s discovery, there were just two exceptions to this rule. The first is a facial tumour that afflicts Tasmanian devils. It spreads through bites, and poses a serious threat to the survival of these animals. The second is a venereal tumour that affects dogs. It arose around 11,000 years ago and has since spread around the world.

That was it: two transmissible tumours. Now, there’s a third—and perhaps more on the way. “Maybe this is way more common than we thought in invertebrates, and especially in marine ones,” says Stephen Goff, who led the study. “We’re all sitting in the same ocean here.”

Goff studies viruses that cause leukaemia in mice. His interest in clams began with a phone call from Carol Reinisch, a marine biologist at Environment Canada. “She said: We have this disease in clams. It’s a leukaemia. Can you help us check if there’s a virus involved?” he recalls. He agreed, and she sent over some blood samples.

The team discovered that the disease is associated with a jumping gene—a stretch of DNA that can copy and paste itself into a new part of the clam genome. They called it Steamer. Healthy clams have between 2 and 10 copies of it in their genomes, but the ones with leukaemia have between 150 and 300 copies. Perhaps some virus was causing Steamer to multiply extravagantly. As it jumped into new places, it disrupted important genes, and triggered cancer. Here was “an example of catastrophic induction of genetic instability that may initiate or advance the course of leukaemia,” the team wrote.

If this idea is correct, Steamer should jump into different positions with each new affected clam. Instead, the team found Steamer in many of the same positions in clams from New York, Maine, and Prince Edward Island in Canada. “That’s when we were really surprised,” says Goff. “There was something fishy going on.”

Next, they compared other positions in the genomes of healthy clams, diseased clams, and tumour cells. Right away, they saw that all the tumours are genetically identical, and none of them matched the genes of their host clams. That’s the same pattern that scientists see in the dog and Tasmanian devil tumours. It’s a clear signature of a contagious cancer. These tumours hadn’t arisen in their hosts; they had arrived there.

“It certainly fits,” says Anne Boettger from West Chester University, who has studied the clam cancer. Still, she notes that Steamer’s positions aren’t always the same in all the clams. There are some variations between animals at different sites, and that’s still unexplained.

The discovery does raise more questions than it answers. For example, when did the cancer originate? The dog tumour is several millennia old, while the devil tumour arose just a few decades ago. The clam cancer was certainly discovered in the 1970s, but it may be much older than that.

How did a normal clam blood cell turn into cancerous one, and how did that leukaemia gain the ability to spread? Was Steamer responsible? “We’re very eager to know,” says Goff. “Did the expanding copy numbers [of Steamer] cause the tumour or are they simply passengers? I think it’s likely that one of these new copies is the cause.” His team are now trying to recreate those original events, by deliberating introducing Steamer into new places in normal clams and seeing if new tumours arise.

How is the cancer spreading? Unlike dogs and devils, clams aren’t mounting or biting each other. But they are filter-feeders: they sieve bits of food from the water, so they could easily draw in floating cancer cells too. Certainly, the disease can spread between animals that share the same aquarium tank, even if they aren’t touching. “It’s not efficient or quick but in the course of months, it happens,” says Goff. It’s a terrifying thought: transmissible cancer in the water. Thankfully, it’s just the clams that are affected.

Or is it?

“We are actively looking in other species too,” says Goff. “There are leukaemias like this in other molluscs in Europe.” In his paper, he already hints that he has discovered a contagious cancer that affects cockles. He also wants to know if these cancers can spread from one species of shellfish to another.

“We normally think of cancers as evolutionary dead ends that emerge and die within the confines of their hosts’ bodies,” says Elizabeth Murchison from the University of Cambridge, who studies the Tasmanian devil tumour. “However, we now know of three runaway cancer clones which have evolved the potential to survive beyond their hosts and become parasitic clonal cell lineages. Understanding how clonally transmissible cancers emerge, spread and escape the immune system may help us to understand fundamental mechanisms of cancer evolution.”

Reference: Metzger, Reinisch, Sherry & Goff. 2015. Horizontal Transmission of Clonal Cancer Cells Causes Leukemia in Soft-Shell Clams. Cell http://dx.doi.org/10.1016/j.cell.2015.02.042

More on contagious cancers:

The Tumor Within A Tumor

Biologists who study cancer have been borrowing a lot of concepts from evolution in recent years. That’s because the changes that occur inside a tumor bear some striking resemblances to what natural selection does to a population of animals, plants, or bacteria. Evolutionary biologists who study societies–from human tribes to ant colonies–have investigated how cooperation can evolve when cheating can let some individuals get ahead. Now scientists are finding evidence of cooperation and cheating among cancer cells. In my column this week for the New York Times, I look at the social life of cancer–and how we might undermine it to fight the disease.

This video, made by the authors of a new study I write about in the column, presents the gist of this idea–of killing a tumor by creating a new tumor inside of it.

Dunharrow from Dunharrow on Vimeo.

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A Floating Autobiography of a Cancer

I’ve written a feature for Nature News about a new way of monitoring and studying cancer, by tracking fragments of DNA that are released by tumours and travel around in the blood. This “circulating tumour DNA” can give away the presence and progress of a tumour. It also allows clinicians to study a cancer patient’s mutations, and potentially better tailor their treatments, without having to perform invasive (and often uninformative) biopsies.
Here’s a teaser; head over to Nature for the full story.

When cancer cells rupture and die, they release their contents, including circulating tumour DNA (ctDNA): genome fragments that float freely through the bloodstream. Debris from normal cells is normally mopped up and destroyed by ‘cleaning cells’ such as macrophages, but tumours are so large and their cells multiply so quickly that the cleaners cannot cope completely.

By developing and refining techniques for measuring and sequencing tumour DNA in the bloodstream, scientists are turning vials of blood into ‘liquid biopsies’ — portraits of a cancer that are much more comprehensive than the keyhole peeps that conventional biopsies provide. Taken over time, such blood samples would show clinicians whether treatments are working and whether tumours are evolving resistance.

As ever, there are caveats. Levels of ctDNA vary a lot from person to person and can be hard to detect, especially for small tumours in their early stages. And most studies so far have dealt with only handfuls or dozens of patients, with just a few types of cancer. Although the results are promising, they must be validated in larger studies before it will be clear whether ctDNA truly offers an accurate view — and, more importantly, whether it can save or improve lives. “Just monitoring your tumour isn’t good enough,” says Luis Diaz, an oncologist at Johns Hopkins University in Baltimore, Maryland. “The challenge that we face is finding true utility.”

If researchers can clear those hurdles, liquid biopsies could help clinicians to make better choices for treatment and to adjust those decisions as conditions change, says Victor Velculescu, a genetic oncologist at Johns Hopkins. Moreover, the work might provide new therapeutic targets. “It will help bring personalized medicine to reality,” says Velculescu. “It’s a game-changer.”

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2 Nearby Towns. 25-Fold Different Stomach Cancer Rates. Why?

One of our oldest companions is a microbe called Helicobacter pylori. It has been colonising our stomachs, and co-evolving with us, for the past 100,000 years. It was with us when were still confined to Africa, and came along for the ride as we spread throughout the world. You can actually trace how humans spread through places like the Pacific islands by comparing the strains of H.pylori in the stomachs of their modern descendants.

H.pylori is the main cause of stomach cancer. But most people who carry the bacterium—that is, half the world’s population—suffer no ill effects, except for some low-grade inflammation. This may be because we have such a long history of co-evolution with this microbe. We have come to a peaceful understanding with one another.

But in some parts of the world, this relationship breaks down. When the European conquistadors came to Central and South America, they brought their own strains of H.pylori with them, and many of these replaced the strains carried by native Amerindians.

This historical mismatch still persists today, and could be seriously affecting the health of modern South Americans.

By studying people from two Colombian town, Tuquerres and Tumaco, a team of scientists led by Pelayo Correa has found that when H.pylori strains share a different ancestry to their hosts, they are more likely to cause cancerous stomach lesions.

According to their study, these incompatibilities between humans and H.pylori  largely explains why the two towns have 25-fold differences in their stomach cancer rates, even though they are just 200 kilometres apart.

I’ve written about this fascinating story for Nature News, so head over there for the details.

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Three Cancer Drugs Don’t Work Properly Without Gut Bacteria

Your gut is home to tens of trillions of bacteria. Collectively, they act as another organ, one with many different roles. They influence your body weight, your ability to digest your food, your risk of catching infectious diseases, your chances of resisting infections or autoimmune diseases, the development of your brain, and more.

Now, we can add an entry to this growing list. At least in mice, gut bacteria can influence whether cancer treatments work.

Working independently, two teams of scientists showed that three cancer treatments rely on gut bacteria to mobilise the immune system and kill tumour cells—not just in the gut, but also in the blood (lymphomas) and skin (melanomas). Remove the bacteria with antibiotics, and you also neuter the drugs.

“It was a surprise,” says Romina Goldszmid from the National Cancer Institute, who led one of the studies. “Nobody would ever have thought we should worry about gut bacteria when thinking about treating cancer.”

The first team, led by Goldszmid and Giorgio Trinchieri, treated tumour-ridden mice with immunotherapy—a cocktail of substances that stimulates the immune system to attack cancer cells. The cocktail shrank the tumours, and prolonged the rodents’ lives. Two months later, around 70 percent of them were still alive. But if the mice drank a cocktail of antibiotics a few weeks earlier, the immunotherapy no longer worked. It failed to keep the tumours in check, and at the two-month mark, only 20 percent of the mice were alive.

The team showed that the gut bacteria stimulate immune cells that live inside the tumour, priming them to respond to immunotherapy. Think of the bacteria as cocking the pistol, while the immunotherapy pulls the trigger. Without that first step, nothing dies.

Goldszmid and Trinchieri’s team also tested a different cancer drug called oxaliplatin, which is used to treat cancers of the bowel, stomach and gullet. It works by damaging DNA, which supposedly prompts cancer cells to release a powderkeg of oxygen molecules. These are so chemically reactive that they wreak fatal havoc inside the tumours.

But the team found that the cancer cells themselves only produce a fraction of these killer molecules. The rest come from the immune cells that live among them. And once again, these cells only did their job if they primed for action beforehand by the gut bacteria. When the team killed the bacteria with antibiotics, oxaliplatin lost its sting.

Meanwhile, the second group led by Laurence Zitvogel from the Gustave Roussy Institute in France tested a drug called cyclophosphamide or CTX, which is used to treat breast cancer, lung cancer, and more. It seems to recruit two types of immune cells called TH1 and TH17 cells which cooperate to attack the tumours. Scientists have known about this immune response for decades, but Zitvogel’s team found that it happens for unexpected reasons.

Cyclophosphamide damages the layer of mucus that coats the intestines, allowing bacteria that live in the mucus to move deeper into the gut. Some of them travel into the spleen and the lymph nodes, where they nudge the resident immune cells into becoming TH1 and TH17 cells. So, cyclophosphamide does its thing by making the gut leaky, and allowing bacteria to migrate out of it! And once again, when the team killed the bacteria with antibiotics, the cancer-killing immune cells weren’t recruited, and the drug became drastically less effective.

What does this mean for cancer patients? “We have to be extremely cautious,” says Goldszmid. “These were mouse studies. It is now absolutely important that these be corroborated in careful human studies.”

Even if they are successful, putting this knowledge to practical use will be very hard. For example, doctors often treat cancer patients with a wide range of other antibiotics. This helps to deal with existing infections and to prevent new ones, especially after treatments like radiotherapy that can suppress the immune system. Based on the new studies, you could argue that these antibiotic assaults make matters worse, but what’s the alternative? “You don’t want to stop giving antibiotics to people who are immune-suppressed,” says Goldszmid.

Instead, doctors might give their patients probiotics to supplement their impoverished guts with the right bacteria. But, which bacteria? In Goldszmid and Trinchieri’s experiments, mice with lots of Lactobacillus in their guts responded poorly to immunotherapy. But Zitvogel’s team found that two species—Lactobacillus johnsonii and Lactobacillus murinus—were among those responsible for the effects of CTX.

This could mean that the same microbes could strengthen some cancer treatments while weakening others. Alternatively, it could mean that different species within the same groups have opposite effects—there are 25 species in the Lactobacillus group and they could do very different things. “It’s possible that we were not looking at the exact same bacteria,” says Zitvogel.

“Other work shows that the microbiome affects the development of colorectal cancer, and can be associated with more tumours. But here, if you disrupt the microbiome, you change the efficacy of an intervention,” says Christian Jobin from the University of Florida. “The microbiome affects the whole range of the disease from initiation to treatment. Harnessing the power of this knowledge will be very difficult for medicine.”

“For me, the take-home message is that we cannot ignore the gut microbiome and the possibility that it has an impact on the response to cancer treatments,” says Goldszmid.

Reference: Viaud, Saccheri, Mignot, Yamazaki, Daillere, Hannani, Enot, Pfirschke, Engblom, Pittet, Schlitzer, Ginhoux, Apetoh, Chachaty, Woerther, Eberl, Berard, Ecobichon, Clermont, Bizet, Gaboriau-Routhiau, Cerf-Bensussan, Opolon, Yessaad, Vivier, Ryffel, Elson, Dore, Kroemer, Lepage, Boneca, Ghiringhelli & Zitvogel. 2013. The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide. Science http://dx.doi.org/10.1126/science.1240537

Iida, Dzutsev, Stewart, Smith, Bouladoux, Weingarten, Molina, Salcedo, Back, Cramer, Dai, Kiu, Cardone, Naik, Patri, Wang, Marincola, Frank, Belkaid, Trinchieri & Goldszmid. 2013. Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment. Science http://dx.doi.org/10.1126/science.1240527

When You’re A Naked Mole Rat, Why Stop At One Weapon Against Aging?

In June I wrote about the amazing longevity of naked mole rats. These rodents can live for thirty years, whereas their mice cousins can only live two years. One secret to their longevity may be the fact that they’ve never been documented with cancer. As I wrote back in June,  scientists at the University of Rochester found  a gooey protein in the tissues of the rodents that prevents cells from multiplying out of control.

But naked mole rats do more than just fight cancer. In addition to avoiding tumors, they also resist the overall decline seen in other aging mammals. A new study from the same Rochester team may reveal how they ward off aging: they’re very careful about making proteins.

Like other animals, naked mole rats carry DNA that encodes thousands of genes. To make a protein, the mole rat’s cells make a single-stranded version of the corresponding gene (called messenger RNA), which is then grabbed by a cellular factory called a ribosome, which is made up of RNA molecules and proteins. The ribosome reads the messenger RNA and uses the genetic code to pick out building blocks to attach to a growing protein.

If the ribosome picks the wrong building block, a protein may end up with a defective shape and can’t do its job properly. A big part of getting old is the accumulation of these defective proteins. Our cells end up getting worse and worse at all the things they excelled at when we were young. Collagen no longer stretches in our skin; our digestive enzymes no longer break down nutrients as efficiently as before. A number of studies have hinted that we can extend our healthy lifespans by boosting our ability to repair defective proteins.

The Rochester team took a look at how naked mole rats build proteins. They discovered something odd about their ribosomes. All living things use pretty much the same set of RNA molecules in this factory. One of these molecules is called 28S. Naked mole rats have a mutation to the gene for 28S RNA. Instead of producing a single RNA molecule, they break it in two.

To see if two 28S molecules worked differently than just one, the researchers compared how the naked mole rats make proteins to the process in mice. They engineered a gene and inserted it into both species. If a cell made an error at one site in the protein, the protein would give off a flash of light. A cell that always built perfect proteins would stay dark. A sloppy cell would glow.

The scientists found that the naked mole rat cells were much darker than those of mice. They built the engineered protein far more accurately, in other words. Naked mole rats, the scientists found, made anywhere from four to ten times fewer mistakes. Yet the naked mole rats can make their proteins as quickly as the sloppier mice.

The scientists were unable to directly examine the 28S RNA fragments in action, so they can’t say for sure that splitting 28S in two is the reason for the accuracy of naked mole rat proteins. Still, the results offer an intriguing hint that this ugly creature has more than one secret to long life. Whether we can borrow that secret is hardly clear. I for one wouldn’t volunteer to have my ribosomes shattered.

(Reference:  Jorge Azpurua et al.“Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage.” PNAS 2013)

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Smart Knife Helps Surgeons Cut Cancer

Cancer is one slippery SOB. It can appear mysteriously, then hang out, thrive, and grow for ages without being spotted. When it is detected, cancer is often unpredictable: It can be fatal, it can be harmless. When under attack, it doesn’t easily fall. Radiation, chemotherapy, and other drugs might curb its spread or substantially shrink it, but they rarely wipe it out. Even under the swift and steady surgeon’s knife, bits of cancer manage to escape.

Take breast cancer. Nearly 700,000 women are diagnosed with it every year in the United States and Europe. About half undergo breast conserving surgery, in which surgeons attempt to excise the tumor while preserving as much healthy tissue as possible. The procedure is tougher than it sounds. Surgeons rely on images of the tumor to guide their cuts, but often have trouble determining its precise borders while the patient is on the table. If they’re not sure whether a piece of tissue is cancerous, they can snip it out and send it to a nearby laboratory for analysis. Then they wait, anywhere from 20 minutes to an hour, all while the patient is still under anesthesia, to get the results. It’s no wonder that even the best surgeons can miss part of the tumor; an estimated 20 percent of women who go through the surgery end up repeating it.

Those numbers may improve thanks to a new surgical tool called the iKnife (i for intelligent). As described in today’s issue of Science Translational Medicine, the tool does sophisticated chemical fingerprinting to help surgeons identify — in real time, right there in the operating room — whether tissue is cancerous or healthy.

“With our technology, identification takes a second — actually, 0.7 seconds,” says Zoltán Takáts, an analytical chemist at Imperial College London who invented the new tool. “One can sample thousands of points during a surgical intervention and it still wouldn’t increase the length of the surgery.”

The iKnife in action. Image courtesy of Science Translational Medicine/AAAS.
The iKnife in action. Image courtesy of Science Translational Medicine/AAAS.

Takáts’s story begins more than a decade ago, when as a postdoctoral fellow at Purdue University he came up with an important innovation in mass spectrometry. Mass spec, as it’s often called, is a common method for determining the chemical make-up of a substance. Mass spec can measure traces of illicit drugs in an athlete’s blood, for example, or the type of pesticide residue covering an apple, or the amount of caffeine in a cup of coffee. Before going through mass spec, samples have to be converted from atoms or molecules into ions — a process that used to require vacuum chambers and tedious preparations. But in 2004, Takáts’s team published in Science a way to ionize samples by simply putting them under a gas jet.

Takáts was immediately interested in applying the new technique to the identification of biological tissues during surgery. The method turned out not to work for this purpose, but while he was figuring that out, he generated a lot of excitement from the surgical community. “They were chasing us,” he says, laughing. “They were saying, ‘OK, we understand that you can’t use this method, but can’t you come up with something else which would work?'”

The idea for the iKnife came from the realization that there’s no need to create a tool that ionizes tissue — surgeons already have one that’s used all the time. Its technical name is an “electrosurgical device”; a more descriptive one is “flesh vaporizer”. Since 1925, doctors have been using these small electric wands for cauterizing wounds and performing dissections. “Pretty much in every surgical theater all over the planet you can find it being used on an everyday basis,” Takáts says.

The worst part about these devices is the smoke they produce. “This is really a smoke of burnt flesh. It’s as nasty as it sounds,” Takáts says. But that smelly smoke contains ionized tissue that’s perfect for mass spec analysis.

Over the past several years, Takáts and his colleagues have conducted a series of rodent experiments testing the new tool, which is essentially an electrosurgical wand hooked up to a rolling mass spec machine (see top photo). They found that smoke produced from burning one type of tissue has a different mass-spec signature than does smoke coming from another kind of tissue. More importantly, they found that cancerous tissue leaves a different chemical trace than healthy tissue does.

That makes sense. Most of the chemicals sensed with this method are phospholipids, fat molecules that line the membrane of each cell. Cancer cells are constantly dividing into new cells, which means they’re constantly synthesizing phospholipids. “So the membrane lipid composition of tumor cells will be quite different from healthy cells. This is what allows us to differentiate them,” Takáts says.

In the new study, the researchers apply the technology to human tissues for the first time. They first created a database of chemical signatures gleaned from doing mass spec on thousands of stored tumor samples. The researchers then put all of that data through a complicated statistical analysis to find patterns that reliably distinguished one tissue type from another. Finally, they tested whether those algorithms could correctly identify cancerous tissue as it was being removed, right in the operating room. It worked: The iKnife was used in 91 surgeries, and in every single one, the tissue identification it made in the operating room matched the one made by traditional laboratory methods after the surgery.

The paper is “a tour de force,” says Nick Winograd, a professor of chemistry at Penn State who was not involved in the research. Winograd is an expert in using mass spec to identify biological samples.

Over the years there have been many attempts to get this technology into a clinical setting, Winograd notes. “But so far there hasn’t really been anything that you can really raise your flag about.” Part of the problem, he says, is that these chemical signatures are only subtly different from one another. They’re all made of the same molecules, just in slightly different combinations. “So you really have to be clever in your data analysis if you’re going to find [patterns] that differ in a systematic way from tissue type to tissue type,” he says.

The iKnife is just one example of a bigger trend of metabolic profiling in medical science. Just as geneticists have done oodles of association studies pairing specific genetic variants to this or that disease, researchers hope to find links between chemical signatures and disease. Proponents say that metabolic studies will give even more information than their genomic counterparts, because they are influenced by both genetic and environmental factors. The foods, medications, and chemical exposures we take in every day don’t change our DNA code, but they do leave a chemical imprint in our tissues. “Understanding that interface of genes and environment is absolutely critical for the future,” says Jeremy Nicholson, a chemist who leads the department of surgery and cancer at Imperial, where the iKnife work took place.

Just last month, Imperial launched a multi-million dollar “Phenome Centre” aimed at conducting chemical studies at many levels — on the scale of the individual patient, like the iKnife work, but also at a population scale, comparing chemicals from the blood, urine, and even microbial communities of groups of people over time.

The Centre has 19 high-tech spectroscopy machines, giving it the capacity to perform more than a million discrete assays a year, Nicholson says. The machines are hand-me-downs from the 2012 Olympic Games, held in London. The U.K. spent around $30 million for equipment to screen the thousands of Olympians for illicit drug use, Nicholson says. “They only found 12 people who were cheating.”

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Why Naked Mole Rats Don’t Get Cancer

The problem with writing about the naked mole rat is the long list of bizarre traits that you don’t have space to talk about. For this post, let’s  forget that they look like a wrinkled finger with teeth. Put aside their inability to feel pain in their skin, their tolerance for chokingly low oxygen levels, their bizarrely rubbish sperm or their poor temperature control. Don’t even think about how they live in ant-like colonies, complete with queens and workers. Ignore their ability to live for more than 30 years—an exceptional lifespan for a rodent of their size.

Instead, let’s talk about the cancer angle.

They don’t get it.

No one has ever seen a naked mole rat with a tumour. Scientists have raised large colonies of these rodents and watched them for many years. They’ve never seen an individual spontaneously develop cancer.

Now, Xiao Tian, Jorge Azpurua and Christopher Hine from University of Rochester have discovered one of the secrets behind this exceptional resistance. The team were trying to grow skin cells from naked mole rats in laboratory flasks, when they noticed something weird. The liquid that the cells were growing in would get viscous and syrupy within a few days.

This was because the cells secreted a sugar called hyaluronan, which was thickening the liquid. Hyaluronan is common in the skin, cartilage and other connective tissues of mammals. Like mortar in a wall, it’s one of many molecules that fill the spaces between cells and provide them with support. The naked mole rat makes an exceptionally large version of the sugar that’s over five times bigger than ours. And it has a lot of it.

There are two innovations behind the naked mole rat’s hyaluronan-fest—ineffective versions of the enzymes that digest hyaluronan, and altered versions of the protein that makes it. This hyaluronan-maker, known as HAS2, is made of 552 amino acids. The naked mole rat has altered just two of these, which are always the same in other mammals. These tiny changes were enough to allow it to make a monster hyaluronan.

Andrei Seluanov, who led the study, suspects that the larger hyaluronan physically cages potential cancer cells, preventing them from breaking free and growing into tumours. But it also allows cells to stop each other from growing if they become too crowded. This is called ‘contact inhibition’—it’s why healthy cells form a flat layer if they’re grown in a dish but cancerous ones pile on top of each other.

Based on an earlier study, Seluanov’s team suspected that naked mole rat cells are protected against cancer because they’re especially sensitive to contact inhibition. Now, they’ve shown that large hyaluronan is responsible. The rodents’ cells are very receptive to the sugar; as they get close, hyaluronan sticks to their surface and triggers a genetic programme that stops them from growing.

As a final test of their ideas, the team switched on a couple of cancer genes in naked mole rat cells and transplanted them into mice. Normally, nothing would happen—the cells are that resistant to cancer. But when the team also interfered with hyaluronan, either by stopping its production or boosting its destruction, the naked mole rat cells finally did the unthinkable—they formed tumours.

Seluanov thinks that hyaluronan is probably the naked mole rat’s “primary anti-cancer mechanism”. After all, disrupting it makes the rodent’s cells as cancer-prone as those of a mouse. Not so fast, cautions Rochelle Buffenstein from the University of Texas Health Science Center, who discovered the naked mole rats’ cancer resistance. “This is now the third study to provide a potential mechanism,” she says. “Clearly there are multiple anti-cancer defenses employed in the naked mole rat.” Others might include mass suicide of overgrowing cells, and a tolerance for DNA-damaging oxygen molecules.

So why did this animal evolve its super-sized hyaluronan? The answer might have nothing to do with cancer.  Seluanov says that the large sugars are slightly elastic and surround themselves with water molecules—two properties that make the naked mole rat’s skin very loose and stretchy. This allows it to move through tight underground tunnels without ripping its flanks as it rubs against dirt, rocks or tubers. Perhaps the large hyaluronans evolved as an adaptation for underground life, and a cancer-free existence was just a neat bonus!

Does this discovery mean anything for humans? It’s tempting to think that hyaluronan holds the secret to stopping cancer, but we have to tread carefully. In the early days of hyaluronan research, scientists were confused by the fact that the molecule seemed to both prevent and cause cancer (the Daily Mail would have loved it).

Since then, we’ve discovered that the sugar’s size is responsible for its dual nature. Bryan Toole from the Medical University of South Carolina, who studies hyaluronan, says that high concentrations of the large versions can stop cells from turning cancerous, while smaller versions can actually promote cancer. In a similar way, the large forms tamp down inflammation while the small ones exacerbate it, which may relevant to cancer since inflammation is tied to several tumours. “It’s not clear how the cell distinguishes between the two,” adds Seluanov. That’s something the team still needs to find out.

Reference: Tian, Azpurua, Hine, Vaidya, Myakishev-Rempel, Ablaeva, Mao, Nevo, Gorbunova & Seluanov. 2013. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature http://dx.doi.org/10.1038/nature12234

For more on the naked mole rat, check out Dan Engber’s award-winning piece at Slate.

Correction: An earlier version of this piece suggested that hyaluronan is a protein, which it isn’t. Your friendly neighbourhood science writer regrets the error.

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Disrupting the Stealth Mode of a Contagious Cancer

You cannot catch cancers. For all their terrifying and destructive properties, tumours aren’t contagious. Unlike, say, a viral infection, you cannot transmit cancer to someone else by coughing in their face, or having sex with them, or sharing the same contaminated water. *

But while this is true for humans, it’s not for Tasmanian devils. These scruffy black-and-white Australian mammals are being slowly wiped out by a contagious cancer, which can jump from the face of one devil to another as they squabble and bite each other over food. This parasite started off as a Schwann cell – a type of cell that wraps around neurons outside of the brain. In a single unfortunate devil, this cell turned into a tumour. And while almost all tumours go down with their hosts, this one somehow evolved the ability to jump into another. It became an independent, free-living parasite.

This infectious cancer, known as devil facial tumour disease (DFTD), invariably kills the devils it infects. It causes such large disfiguring tumours that its hosts can no longer eat properly. First documented in 1996, it has since spread to the majority of the devils and threatens to wipe them out entirely within a few decades. Caught off-guard, a small team of scientists is now racing to find ways of saving the devils and to understand DFTD. (Carl Zimmer has a great round-up of their work at the New York Times.)

How could a single cancer spread so effectively among the Tasmanian devils? By right, the immune system of any new host should be able to recognise and kill these invading cells. The people working on the devils had always assumed that their narrow genetic diversity had inadvertently given the tumour a free pass. Ages ago, the devil population crashed, sending them through a ‘genetic bottleneck’. That is, all the living devils are meant to be extremely close relatives. Their immune systems won’t kill DFTD cells because they can’t tell the difference between these invaders and their own tissues.

But that explanation is wrong. The devils actually have plenty of genetic diversity, and their immune systems will reject skin grafts from a different individual. So how does the tumour sneak past?

Hannah Siddle from the University of Cambridge has the answer. Like us, a devil’s cells display proteins called MHC on their surface, which help the immune system to recognise threats like tumours or virus-infected cells. Siddle expected to see that DFTD displays very similar MHC molecules to those of the various devils. She actually found that they don’t display MHC at all.

This isn’t because the genes for these protein have been broken through mutations. Instead, MHC molecules need an entourage of other proteins that escort it from factories within the cell to their posts on the surface. And DFTD cells don’t make any of these escorts. They have a cloaking device that renders them invisible to the immune system.

But Siddle found that they can be persuaded to. When she treated the cancerous cells with an immune chemical called interferon-gamma, they started displaying MHC. That’s big news, and the team is now working to develop a vaccine using this discovery. The idea is to expose healthy devils to DFTD cells that have been treated to  expose their hidden MHC molecules. This would train the immune system to recognise these threats and mount a vigorous defence should the devils ever become infected. It’s an early step, but a hopeful one.

You can read more about this story at Nature News.

Reference: Siddle et al, 2013. PNAS. http://dx.doi.org/10.1073/pnas.1219920110

* You can transmit certain viruses and bacteria that can cause cancer, such as HPV, but that’s not the same as saying that the tumours themselves are contagious.

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What does it mean to say that something causes 16% of cancers?

A few days ago, news reports claimed that 16 per cent of cancers around the world were caused by infections. This isn’t an especially new or controversial statement, as there’s clear evidence that some viruses, bacteria and parasites can cause cancer (think HPV, which we now have a vaccine against). It’s not inaccurate either. The paper that triggered the reports did indeed conclude that “of the 12.7 million new cancer cases that occurred in 2008, the population attributable fraction (PAF) for infectious agents was 16·1%”.

But for me, the reports aggravated an old itch. I used to work at a cancer charity. We’d get frequent requests for such numbers (e.g. how many cancers are caused by tobacco?). However, whenever such reports actually came out, we got a lot confused questions and comments. The problem is that many (most?) people have no idea what it actually means to say that X% of cancers are caused by something, where those numbers come from, or how they should be used. (more…)

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World within a tumour–study shows how complex cancer can be

When I used to work at a cancer charity, I would often hear people asking why there isn’t a cure yet. This frustration is understandable. Despite the billions of dollars and pounds that go into cancer research, and the decades since a war on cancer was declared, the “cure” remains elusive.

There is a good reason for that: cancer is really, really hard.

It is a puzzle of staggering complexity. Every move towards a solution seems to reveal yet another layer of mystery.

For a start, cancer isn’t a single disease, so we can dispense with the idea of a single “cure”. There are over 200 different types, each with their own individual quirks. Even for a single type – say, breast cancer – there can be many different sub-types that demand different treatments. Even within a single subtype, one patient’s tumour can be very different from another’s. They could both have very different sets of mutated genes, which can affect their prognosis and which drugs they should take.

Even in a single patient, a tumour can take on many guises. Cancer, after all, evolves. A tumour’s cells are not bound by the controls that keep the rest of our body in check. They grow and divide without restraint, picking up new genetic changes along the way. Just as animals and plants evolve new strategies to foil predators or produce more offspring, a tumour’s cells can evolve new ways of resisting drugs or growing even faster.

Now, we know that even a single tumour can be a hotbed of diversity. Charles Swanton from Cancer Research UK’s London Research Institute discovered this extra layer of complexity by studying four kidney cancers at an unprecedented level of detail. He showed that the cells from one end of the tumour can have very different genetic mutations to the cells at the other end.

These are not trivial differences. These mutations can indicate a patient’s prognosis, and they can affect which drugs a doctor decides to administer.  The bottom line is that a tumour is not a single entity. It’s an entire world.


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Random gene sets can predict breast cancer survival better than supposedly cancer-related ones

I’ve written a few guest posts for the Faculty of 1000’s Naturally Selected blog, covering some interesting papers from last year that I missed here. There’s one about how eggs greet sperm, and another on how sleeping alone affects newborn babies. But the third post is one that I particularly want to draw attention to – it’s about a cancer paper that didn’t get much notice last year, but seems to deserve it. Here’s the first bit:

Tumours are bundles of cells that grow and divide uncontrollably, and their genes are deployed in unusual ways. By analysing the genes from different tumour samples, scientists have tried to pin down the chaotic events that lead to cancer. They seem to be making headway. Dozens of papers have reported “gene expression signatures” that predict the risk of dying or surviving from cancer, and new ones come out every month.

These signatures purportedly hint at how healthy cells transform into tumours in the first place. If, for example, the genes in question are involved in wound healing, this tells you that the healing process is somehow involved in a tumour’s progression. These collections of genes reveal deeper truths about the disease they’re associated with.

This idea sounds reasonable, but David Venet from the Université Libre de Bruxelles has thrown a big spanner into the works. He has shown that completely random sets of genes can predict the odds of surviving breast cancer better than published signatures.

Venet found three signatures that are completely unconnected to cancer. Instead, these collections of genes were associated with laughing at jokes after lunch, with the experience of social defeat in mice, and with the positioning of skin cells. All of them were associated with breast cancer outcomes.

Head over to Naturally Selected for the rest, including how long it took to get this study published.

Image by Hakan Dahlstrom

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Extending healthy life by getting rid of retired cells

As we get older, many of the cells in our bodies go into retirement. Throughout our lives, they divided time and again, all in the face of radiation bombardments and chemical attacks. Slowly but surely, their DNA builds up damage to that threatens to turn them into tumours. Some repair the damage; others give up the ghost. But some cells opt for a third strategy – they shut down. No longer growing or dividing, they enter a state called senescence.

But they aren’t idle. Senescent cells still secrete chemicals into the body, and some scientists have suggested that they’re responsible for many of the health problems that accompany old age. And the strongest evidence for this claim comes from a new study by Darren Baker from the Mayo Clinic College of Medicine.

Baker has developed a way of killing all of a mouse’s senescent cells by feeding them with a specific drug. When he did that in middle age, he gave the mice many more healthy years. He delayed the arrival of cataracts in their eyes, put off the weakening of their muscles, and held back the loss of their body fat. He even managed to reverse some of these problems by removing senescent cells from mice that had already grown old. There is a lot of work to do before these results could be applied to humans, but for now, Baker has shown that senescent cells are important players in the ageing process.


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From unknown cancer gene to potential cancer drug

It’s a seemingly simple idea: if you can find the genetic changes that turn normal cells into cancerous ones, you could find new ways of treating cancer. But that’s easier said than done. The genome of a cancer cell is a chaotic mess. Typos build up throughout its DNA, corrupting the encoded information. Entire sections can be flipped, relocated, doubled and deleted. Some of these changes drive the cells to grow and multiply uncontrollably; others are irrelevant passengers that are just along for the ride. Separating the former form the latter is like finding a needle in a haystack made of needles.

And that’s exactly what Elisa Oricchio from the Sloan-Kettering Memorial Cancer Center has done. Using powerful genetic techniques, she has identified a gene – EPHA7 – whose loss can lead to a sluggish but hard-to-treat type of lymphoma called follicular lymphoma. The gene encodes a protein of the same name, and Oricchio even used the EPHA7 protein to shrink the size of tumours in mice with lymphoma.


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Genetic logic circuit makes cells self-destruct if they look cancerous

It is easy enough to make software do what you want it to. You could tell your email client to recognise and immediately delete any unwanted messages – say, any from your mother-in-law that contain the word “visit”, but not the word “cake”. Now, Zhen Xie from Harvard University and MIT has found a way of filtering undesirable human cells – in this case, a specific type of cancer cell – with similar ease.

Xie has developed a genetic “logic circuit” that prompts cells to kill themselves if the levels of five molecules match those of a cancer cell. Yaakov Benenson, who led the study, says, “In the long term, the circuits’ role is to act like miniature surgeons that can identify and destroy cancer cells.” That is a very long way off, but the study is a promising step in the right direction.