The Cutting Edge of Cancer Research

04 November 2012
Presented by Chris Smith, Kat Arney.

How does cancer spread? How can we target our immune system to take out tumours? This week we visit the National Cancer Research Institute's annual conference to explore the cutting edge of cancer research. We'll find out why cancers become resistant to chemotherapy, and how new research offers us a window to watch a cancer as it spreads.

In this episode

01:45 - How Cancer Cells Spread

Cancer spread causes 9 out of 10 cancer deaths. We’re joined by Dr. Joan Masague who is trying to understand how cancers spread and how we can tackle it....

How Cancer Cells Spread
with Dr Joan Massagué, Sloan-Kettering Institute

Kat -   Probably the biggest issue in cancer and one that causes around 9 out of 10 cancer deaths is the fact that cancer spreads around the body, forming other tumours elsewhere.  This is a process that scientists call metastasis.  Now we're joined here at the NCRI Cancer Conference by Dr. Joan Masague from the Memorial Sloan-Kettering Cancer Centre in the New York and he's working on trying to understand how cancers spread and how we can tackle it.  So, hello, good evening, Joan.

Joan -   Hello.

Kat -   So, let's start by going back to basics.  What do we mean by a cancer spreading?  What's going on here?

Joan -   Cancer as we know is an abnormal growth that is generated, initiated by just a few cells in a human tissue.  It could be the breast.  It could be the prostate, intestine, anywhere.  A few cells that have accumulated mutations and these mutations allow these cells to begin to break the rules that keep the healthy normal growth of tissues.  These rules include not only growing and proliferating correctly, but also staying put.  The cancer cells have the ability to move away, to walk away, and as the tumour grows and the blood vessels are attracted to feed the growth of this tumour, cancer cells find their way into the circulation.  Circulation carries them away. In distant organs these cells may, by virtue of their ability to walk, to infiltrate, to invade, come out of the circulation again, enter the distant tissue that could be the liver, the lung, the bone marrow, the brain, and try and resume cancer growth there.  This whole process is what we call metastasis.

MetastasisKat -   So, we've got these naughty cells, not knowing that they should stay in one place and spreading, and forming new tumours, why is this such a big problem in cancer?  Why is this?  Why does this make cancer so hard to treat?

Joan -   Of course, with the spread of cancer, we have not one tumour only that is localised and can be removed in the operating room, we now have other tumours in many other places.  Not only that, but these tumours are created by the nastiest of the nasty.  Those cells that were able to leave the primary tumour, the origin tumour, find their way to distant places, resist having invaded an organ, a tissue that they're not accustomed to, and so forth.  So, the cells that undergo this process are more aggressive and are going to be even more resistant than the original tumour to any therapy that we try.

Kat -   These are really evil, nasty cancer cells then.  So, I remember reading about a guy over 100 years ago - Paget I think his name was - who had the idea of the seed and the soil.  So the cancer cells that spread are like the seed and they go around the body looking for soil they like to grow in.  What do we know about the types of places that cancer cells spread?  Is it the same places like a cancer will always go to, the brain or the lung, or is it different?

Joan -   Well, we know from patients who have cancer that every type of cancer has a different predilection for metastases to different organs.  And so, the question is why?  The way we now think about these, based on the results of research is that of course, when cells leave a tumour, they go everywhere.  The circulation takes them everywhere.  What we mean by growing in one place is that they die everywhere, but they die less.  They have more chance in a given organ than another because they are somehow primed to thrive there with more probability than in another distant organ.

Kat -   So I guess this is a bit like a dandelion or something, sending all of these seeds out and most of them will never ever grow, but just a few of them do.  What do we know now about why some of these cancer cells do manage to grow in some places?  What's going on?

Joan -   We know the about the molecules and genes, and processes that allow these cells to go through a series of bottlenecks that they face in order to invade a given organ.  First, they have to come out from the circulation into that organ.  The blood vessels are different organs, so the cancer cells in the circulation to begin with, they need different skills to get into an organ or another.  Second, they have to resist the shock of entering an organ that they have never seen before.  And so, that immediately selects for cells that were prepared to deal with that new environment and finally, to overtake.  Not just to resist, but actually, to take over that organ.  That too, needs a different set of skills.  So, we've identified genes and molecules that allow the cancer cells in any given organ to go through each one of these bottle necks.

Kat -   And of course, it's great to identify all these factors, the molecular factors, the genes, and the molecules.  How are we trying to turn this knowledge into new ways of treating cancer that has spread because it still does claim so many lives?

Joan -   Yes, and 90% of lives claimed by cancer is through this process of metastasis.  We are learning a lot about the biology and about these different molecules, and the steps that I was talking about.  What we want at the end is the common nexus, those molecules and genes that allow the majority of cancer cells to be metastatic to many different places.  These are ones that have the highest clinical value and then with this knowledge, developing drugs that interfere with the ability of cancer cells to set shop anywhere or in as many places as possible to have the most effective drugs.  The drugs with the widest spectrum of possible benefit.

Kat -   And just to end really briefly, we've spent so many years, so many decades researching cancer.  How close do you think we are to actually really making breakthroughs in treating a cancer that has spread?

Joan -   I think we are already making great success because many cancers, 50% or more are cured.  Metastasis however is the last bastion and is the most difficult segment of the disease and this is what a large community now has engaged itself in conquering.  So, we are going to be seeing, I'm sure over the next years and decades, progressive resolution of this problem.

08:35 - Has cancer always existed?

Has cancer always existed?

Kat - I can answer this with my day job hat on, working for Cancer Research UK. Cancer has pretty much always been with us and it's a disease that can affect any multicellular organ or organism because it's just caused by cells going wrong.

So we know for example that plants can get cancer, all kinds of animals can get cancer. Most of them don't seem to live long enough to get it, but it's a disease that has always been with us. There's evidence from things like dinosaur bones and fossilised human remains, and even before that, Neanderthal remains, that cancer has always been a disease that's affected us. So, it's pretty much as old as you like really.

Chris - Just to pick you up on the plants thing of course, they won't have a multisystem type problem that a person with cancer would have. They wouldn't get spread necessarily for tumour to other bits of the plant, would they?

Kat - No, but they get - if you've ever seen a big sort of bulging gall on the plant. That's basically a plant kind of tumour because something has hijacked the cells of that plant and made them grow out of control which is basically what's going on in cancer - either the genes have become faulty or in the case of some viruses, they've hijacked the cells and are making them grow. But cells growing out of control are cancer and pretty much any complex organisms will get it.

10:06 - Overcoming Treatment Resistant Tumours

One of the key problems in the treatment of cancer is that tumours, having initially responded very nicely to a course of chemotherapy can often subsequently become resistant to that same...

Overcoming Treatment Resistant Tumours
with Dr Simon Cook, Babraham Institute

Now, one of the key problems in the treatment of cancer is that tumours, having initially responded very nicely to a course of chemotherapy, can often subsequently become resistant to that same treatment which makes the cancer much harder to manage.  To explain how this happens and how we might be able to overcome the problem, Dr. Simon Cook works at the Babraham Institute in Cambridge joins us.

Chris -   First of all, tell us a little bit about why a cancer does that?  Why do people start off responding very nicely to a drug and then their cancer comes back, and now, it won't respond?

Simon -   Cancer is driven by the activation of specific Angel Undergroundsignalling pathways in the cell and some of the new drugs which are being used to treat cancer now inhibit these specific pathways.  The analogy I like to use is if you arrive at King's Cross St. Pancras and you want to go by underground to Leicester Square, if Russell Square is closed then you can't get through.  The analogy there is that the new drugs are like blocking Russell Square so you can't go through the Piccadilly Line down to Leicester Square.  The point is that tumours are tenacious in their ability to get around these blocks and so, they'll just hop on a different train and go to Euston and then come down the Northern Lane to get to Leicester Square.  So, there is heterogeneity in tumour cells and tumour cells which respond very well initially to drugs which inhibit the Piccadilly line for want of a better phrase, will switch over and select out to use a different pathway to maintain cell proliferation, cell division and cell survival.

Chris -   So, when someone has a tumour, if we were to look at the cells in that tumour, we wouldn't see one type of cell only.  We would see a mixture of the cells with many different genetic changes, making them all behave in a very different way.  So, when we throw drugs at it, the ones that are sensitive to that drug will be killed or inhibited, but this will select out a population of cells that just by chance happen to have genetic changes that have - as you've put it quite nicely there - got the ability to jump on another train and take them around whatever that blockade the drug is imposed is.

Simon -   That's absolutely correct and in many senses, this is sort of Darwinian evolution taking place at the cellular level that you need two basic ingredients for evolution.  You need genetic heterogeneity and you need a selection pressure.  The genetic heterogeneity is in the tumours.  We know from increasingly advanced methods for analysing tumour genetic mutations that there are really thousands and thousands of genetic mutations in each individual tumour, and the selection pressure is some of the new drugs that we're adding, and you're absolutely right, the vast majority of the cells die, but a very small subset essentially seed for regrowing, and taking that different path.

An assortment of drugsChris -   So when someone is put on therapy and they've got a cancer to start with, it's going to have a mixture of these different genetic changes, making it sensitive to some things and not others.  Does this mean then that just going in with one drug is a flawed strategy because comparing it with say, treating a virus infection, we know that if you used just one drug in people who have HIV then you very quickly get viruses coming out which can just bypass that drug in the same way?  The way that virologists get around this is to put patients on several drugs at once to make it much harder.  So is that what cancer biologists are, or need to be doing?

Simon -   Yes, very much.  So, there are some cancers which are almost single-gene diseases.  Perhaps the best example is chronic myeloid leukaemia where that is very much driven by a single gene and there are now very good drugs which inhibit that and make that to a great extent a manageable disease.  But for many other cancers, because of these multiple mutations, yes, I think increasingly the way to go is going to be using combinations of different drugs which target these different signalling pathways inside the cell.

Chris -   So, tell us a bit about your work in the sense that you're saying you're now trying to dive inside the cell, and unpick some of these - for want of a better phrase - tube maps to see how cells are doing what they're doing to find out ways of stopping them doing this train jumping trick.

Simon -   That's exactly right.  So, we're growing human tumour cells in the laboratory and we're treating them with some of the very new specific drugs, and we're generating resistant human tumour cell lines in the laboratory then actually analysing how they've remodelled their tube map, how they remodel their signalling pathways, which pathway they're now using, is that pathway a pathway which we can inhibit with another drug so that if we can understand how tumour cells respond and react, and acquire resistance to drug A, and if we can identify the mechanism by which they're doing it, then that may actually validate using drug B as well.

Chris -   What about the fact that many cancer biologists will say that a common misconception is to call cancer one disease?  There are many, many different types of cancers in different types of tissues which can all have different origins, and therefore, one drug does not treat all.

Simon -   That's absolutely true.  I think this is perhaps an area where the general public are less aware that in fact, for example, lung cancer is not just one form of cancer.  There's non-small cell lung cancer and there's small lung cancer.  There are now, for some forms of non-small cell lung cancer, very good drugs which can often give quite good responses, but those drugs are no good against small cell lung cancer.  The same applies with breast cancer, the same applies with colorectal cancer.  These different types of colon cancer are driven by different driving oncogenes; different driving cancer genes and therefore, drugs which work for one form won't necessarily work for another.

Chris -   So, this whole idea of personalised medicine and tailoring therapies to individual diseases is probably the way it's got to go, but it's going to get very costly.

Simon -   Undoubtedly, yes.  I think some people speculate that in the future, a patient coming in to the clinic to start with will have that tumour typed to work out which mutations are there and this will tailor them to a particular drug or combination of drugs.  And presumably, that will happen for every person because it will potentially be different for every person.  And by necessity therefore, it's taken a lot of time and effort, and money to generate these drugs and so, I guess understandably, drug companies are going to want to see a return on that investment.

Chris -   Some people say, just to finish this off, there's never been a better time to get ill, really.  Would you agree?

Simon -   I think it's a very exciting time in cancer therapy because we're seeing a return of 20 years, 25 years of research to actually understand what's causing cancer.  We now understand in many cases and we now have very good therapies coming through because of that understanding.  So yes, I could see why they might say that.

16:38 - Easy Peel Medical Tape

Medical tape that sticks strongly but peels off with less force than it takes to tear tissue paper has been invented by scientists in America...

Easy Peel Medical Tape

Medical tape that sticks strongly but peels off with less force than it takes to tear tissue paper has been invented by scientists in America.

Medical adhesives cause millions of injuries each year, often when used on frail elderly skin, or on tender newborns and premature babies.  This happens because the present generation of medical tapes consist of a strong backing, usually made of PET, applied to an adhesive.  And because it takes more force to pull the tape off than it takes to physically tear skin, the result is frequently trauma and even scarring.

Albupore surgical tapeNow scientists at Harvard medical school has found a way to produce a "quick release" form of tape that is extremely strong but can even be peeled away from delicate origami paper without ripping it.

Michael Karp and his colleagues, writing in PNAS, have hit upon the idea of introducing a non-stick silicon polymer "release layer", which is sandwiched inside the tape between the adhesive and the backing.  This is designed to break when minimal upward force is applied, allowing the backing and the glue to separate.  The adhesive remains temporarily stuck to the skin after removal of the tape, but without the backing to spread the load it can readily be rubbed away with a little talcum powder.

The key to making the idea work was to use a laser to cut a grid pattern into the silicone release layer.  This allows sufficient contact between the adhesive and the PET backing for the tape to work stably and resist forces at the skin surface, meaning that medical instrumentation and dressings are firmly held, but tugging upwards on the backing breaks its weak association with the adhesive and the two part company.  And because the new tape is largely made of all the same materials routinely employed in medical tapes, and the laser technique is standard practice, scaling up production and introducing the new material clinically should be simple.

18:59 - Can Koshik the elephant talk?

Dumbo the elephant may have been able to fly, but he was fictional. Now a team of German, US, Korean and Sri Lankan researchers believe that they may have found an elephant that can talk –...

Can Koshik the elephant talk?

Dumbo the elephant may have been able to fly, but he was fictional. Now a team of German, US, Korean and Sri Lankan researchers believe that they may have found an elephant that can talk - or at least make vocal sounds that convincingly resemble human speech.

Asian ElephantThis talented animal is called Koshik, a 22 year old Asian elephant who was born in captivity and moved to Everland Zoo in South Korea when he was just three years old, though he has been the only elephant in the zoo since 1995. Writing in the journal Current Biology this month, Angela Stoeger and her colleagues, recorded clips of Koshik making unusual noises which his trainers thought sounded like Korean words, and played them to 16 different native Korean speakers, to see if they could pick out which words he was apparently saying. The scientists found that Koshik can imitate at least 5 Korean words pretty well, including hello ("annyong"), no ("aniya") and  sit down ("anja"), although his vowel sounds are much better than his consonants.

How's he making these noises - elephant mouths are quite different from our own, aren't they?

An elephant's mouth is very different from our own, and their vocal tract is much longer than ours. To imitate the sound of human speech, Koshik puts the tip of his trunk into his mouth to change the shape of his vocal tract - something that's never been seen in an elephant before. And the only other animals that are known to change their vocal tracts in this way are orangutans, who use their hands or leaves to change the sounds they can make.

Why would animals imitate human speech? Are there any other animals that can do this?

This is the first documented example of an elephant mimicking human speech -although there are unconfirmed reports of an elephant in Kazakhstan that could "say" Russian and Kazakh words - there are a few other animals that can imitate speech. Two obvious examples are Mynah birds and parrots, but there's also the case of Hoover the seal, who was taught human phrases by a fisherman, and Logosi the beluga whale who could say his name. Interestingly, attempts to teach chimps to imitate human speech have mostly failed, even though their vocal apparatus is similar to our own, suggesting that it's not the equipment that an animal has that's important for mimicking human speech, but something to do with the way their sound perception and production pathways are wired up to the brain. 

As to why animals might imitate human speech, it's hard to know. The researchers suggest that the fact that Koshik was reared in captivity, and has been the only elephant in the zoo for a long time may have something to do with it. In the wild, animals including elephants mimic each other's vocal sounds as part of forming social bonds and groups, so maybe Koshik is just trying to bond with his keepers.

21:53 - Fireflies inspire brighter LED's

The light-emitting tails of fireflies have revealed a way for scientists to create more efficient LEDs.

Fireflies inspire brighter LED's

The light-emitting tails of fireflies have revealed a way for scientists to create more efficient LEDs. By studying the tails of the firefly Luciola lateralis under an electron microscope, Korean researchers noticed that the surface layers of the parts of the insects' bodies that illuminate when they power up their internal lanterns are shaped very differently from those covering the rest of the abdomen.

Non-illuminating regions of the firefly body show a surface contour that lacks Firefly (species unknown) captured in New Brunswick, Canadaany obvious regular shape or pattern, Jae-Jun Kim and his colleagues at the Korea Advanced Institute of Science and Technology found. But the lantern segments were covered in a series of straight ridges and folds running in parallel and each about 1/7000th of a millimetre high.

This structure, the team have shown, works in the same way as the anti-reflective coatings added to camera and telescope lenses and ensures very efficient light extraction from the insect's light organ into the air. Because LEDs are structured similarly to the firefly lantern, with a light source placed in front of a reflective layer and with a lens in front to funnel out light, the team wondered whether equipping LEDs with the same surface structure as the firefly tail could make for brighter LEDs.

By etching silicon, they created the equivalent of a nano-patterned jelly-mould capable of reproducing plastic LED lenses with surfaces mimicking the nanostructures on the firefly's tail. Added to LEDs, these insect-inspired lenses were immediately 3% brighter than the traditionally constructed counterparts.

"This biological inspiration can offer new opportunities for single step and low-cost moulded lenses with high transmission power in high-power LED applications, such as liquid crystal display backlight units, mobile camera phone flashes, automotive, domestic and medical lighting,"

say the team, in their paper published this week in the journal PNAS.

doi: 10.1073/pnas.1213331109

24:10 - Pre-Historic Dairy Cows - Planet Earth Online

Cows milk is a remarkable food – not only for drinking, but for cheese and butter, yoghurt and cream. So when did we first decide to use cows as walking larders to fulfil our nutritional...

Pre-Historic Dairy Cows - Planet Earth Online
with Julie Dunne, University of Bristol

Cows milk is a remarkable food - not only for drinking, but for cheese and butter, yoghurt and cream. So when did we first decide to use cows as walking larders to fulfil our nutritional needs?

Scientists from the University of Bristol have analysed pots found in, what is now, the Sahara Desert in Libya but - thousands of years ago - was verdant countryside.

By studying chemical residues found in these containers, they've discovered the first direct evidence that people in Africa were using cattle for milk more than 7000 years ago.

Planet Earth podcast presenter, Richard Hollingham, has been talking to archaeological scientist Julie Dunne, at the University's farm in Somerset....

Julie -   Well, what we looked at was lipids in ceramics that were excavated from the rock shelter in the region and those lipids tell us that those people were using milk products and also animal fat products and processing them in their pots.

Richard -   And they were using this milk for what?

Julie -   Well it probably would have been making butter, cheese and yoghurt.  We could tell it was processed in the pots and the reason they would have probably processed it is because most humans are... well humans then were lactose intolerant, in other words they couldn't drink milk, they would have been quite ill, they would have had very unpleasant symptoms.  If you process milk that reduces a lot of the lactose content and they could have eaten it without becoming ill.

cow and zebraRichard -     These pots were from 7,000 years ago, so pre-history and in that time we've managed to evolve the ability to digest milk?

Julie -   Yes, it's quite remarkable. It's a very good example of selection in action. Around about 10,000 years ago when people started dairying and settled down living a farming lifestyle as opposed to being hunter gatherers nobody could tolerate milk.  But obviously the new technology comes in and there are these wonderful creatures called cows, they are walking larders and people obviously want a bit of this new technology. They're like an iPad of the ancient world and once you start processing these milk products and using them, within about a thousand years a gene evolves which allows people to tolerate milk so we've become lactose persistent.

Richard -   How do you know they were after the milk rather than milk as a by product, that milk was the key to this?

Julie -   We can identify whether they were processing either milk or the fats from the animal, the flesh of the animal in the pots.  When we did what we call lipid analysis, 50% of the pots showed evidence that milk was processed in them. So it was clearly important to these people.  Bear in mind that region, although it had been quite green and wet in the last ten thousand years it was beginning to dry up, and as cattle start to come into the area you are getting these periods of aridity.  Cattle are important because they're a source of liquid on the hoof as it were, so these people were moving around the landscape with their cattle and if there wasn't any water they would be able to get a drink from the cattle.

Richard -    So the cattle became much more valuable for producing milk than they did for meat or by products like skins or whatever?

Julie -   Yes, we think so, we think so. We think it's what we call the secondary products of the animal, the milk, the cheese, the butter, the yoghurts; those are the things that were much more important to ancient people rather than the actual flesh of the animal. Why would you kill something that is going to give you food every day?

Richard -   What sort of difference did this make to humans and human civilisation?

Julie -   The transition from becoming hunted gatherers to settling down - it enabled the development of much bigger communities and so on which eventually led to the establishment of things like city states and so on and so on and finally to where we are today.

Richard -   So this was happening in Africa - how did we end up here farming cows, drinking milk, making cheese, all this stuff?

Julie -   Yeah, we really do so a kind of different pattern emerging in Europe, so cattle were actually domesticated in Europe, we think, and they moved into Africa but they also moved with people the other way and spread out right across Europe and into Britain and Ireland finally getting here round about 4,000 BC, so six thousand years ago.  Pretty much across Europe people settled down, they became farmers and they started using milk and its products.

Richard -   So cattle turn out to be incredibly important for these prehistoric people and for the development of humans, and they're still important today?

Julie -    Absolutely, yes. These cattle were incredibly important to these ancient humans. For a start they created the most remarkable rock art which shows how much they clearly thought about and relied on their animals. They were clearly just as important then as they are today.

28:55 - The Benefits of Breast Cancer Screening

Is breast cancer screening beneficial? A paper in the Lancet this week examines the pros and cons...

The Benefits of Breast Cancer Screening
with Professor David Cameron, The Edinburgh Cancer Research Centre

Is breast cancer screening beneficial?  A paper in the Lancet this week examines the pros and cons...

Professor David Cameron at Edinburgh University is one of the authors on that paper.

David -   There has been for some time, a controversy in the area of whether women should undergo regular mammographic screening to try and pick up cancers before they are obvious to the patient or the doctor.  The controversy has really ended up with two polarised views.  One saying, this process works.  It prevents women dying earlier of breast cancer and another view that says, it picks up lots of cancers that never needed to be found, doesn't make much difference to whether women survive breast cancer and therefore, should be stopped.

Chris -   So you were then consigned the unenviable task of looking at this data to try to answer that question.  Not an easy job to do.  How did you do it?

Normal (left) versus cancerous (right) mammography image.David -   We focused on two key points.  What were the mortality benefits and what were the harms?  Particularly the harm of what's called 'over diagnosis' and that is a technical term.  What it means is a cancer that is found through screening, that is a real cancer, but it's a diagnosis of a cancer that would not have otherwise come to light or cause clinical problems in a woman's lifetime.

Chris -   How do we know that a cancer detected at stage X would not have killed that person?

David -   For an individual woman and then for her individual cancer, we cannot.  And so, you can only deduce the existence of this group of cancers through the analysis of pooled data, either from randomised trials or from observational studies.

Chris -   And how did you do that?

David -   The approach we took was to first go back to randomised controlled clinical trials.  The big advantage of a randomised trial is that provided it's reasonably well-designed.  The only difference between the two groups of women is whether or not they have mammographic screening.

Chris -   Because what one doesn't want to do and this has been a certain criticism levelled that some of the data from America for example with things like prostate cancer, where America is extremely proactive about screening people and then diagnosing, and treating people with prostate cancer, people have said there's a lead time bias.  You diagnose people and actually, you look like you're achieving an incredible response rate, but were those cancers not picked up until later and then treated anyway, the people would have ended up with the same outcome.

David -   Exactly and we did look at quite a lot of observational data and some of the observation studies have been very well conducted in a sense that the authors have tried everything they can to control for things like lead time and underlying differences in breast cancer incidents.  But they all tend to rely on some key assumptions including what would have happened in that population, had breast screening not been conducted.  We did an interesting modelling exercise changing various assumptions, but working on the same dataset, and showed you could draw quite different conclusions.

Chris -   How did you draw the conclusions that you did?

Breast self-examinationDavid -   Let me address the question of how we came to the conclusion that breast cancer screening does reduce the mortality for breast cancer.  We took the hazard ratios for breast cancer screenings from these trials where we had 13 years of patient follow up after the end of the trial.  Because if you're going to catch a cancer early in order to reduce a chance of a woman's dying, you need to measure her risk of dying from breast cancer.  Not just during the trial, but for many years after.  Now, our conclusion was that there was a 20% reduction in breast cancer mortality in these trials.

Chris -   How many lives saved does that turn into?

David -   Well, what we then did was to say, let's look and see what happens in the UK where we have a 20-year breast cancer screening programme for women, age 50 onwards.  We took their risk of dying of breast cancer between the ages of 55 and 79, and so, we back-extrapolate it to work out what the mortality would be without that 20% reduction, which works out at about 1300 women a year not dying from breast cancer because of breast cancer screening.

Chris -   What about the converse which is, people have picked on the number which has appeared in the paper in the Lancet saying, "Look, there are thousands of people who are now having interventions that they needn't have done."  What can we say about that group?

David -   We took the same approach.  We started with our randomised trials, but critically, if you're going to measure over diagnosis, you need to have a control group who are never screened, and many of the studies offered or systematically screened the women in the control arm at the end of the trial.  So we took the only trials where there was no exit screening.  So that left us just 3 trials to look at for our estimate of over diagnosis.  So we took these 3 trials and we estimated the risk of an over diagnosed cancer and our conclusion was that in the UK approach to screening, that about 19% of the cancers found during the time of screening would be an over diagnosis.  That translates to a figure of about 4,000 women a year, but the precision of that figure is less than the precision for our mortality benefit.  But nevertheless, it is a real number of patients who have a cancer that they didn't need to know about.

Chris -   And what are the implications of these numbers?

David -   The significance of the over diagnosis number is firstly that women need to be aware that this is a risk or a price that they have to pay if they're going to undergo screening.  They may have something found that wasn't necessary to be found.  However, we can never work out who they are, so they need to continue to be treated exactly the same way.  But it offers an opportunity for research to further explore how we could identify these cancers that we didn't need to discover.  From the mortality point of view, our primary conclusion was that the breast cancer screening programme should continue because we felt 1,300 lives a year was well justifying the continuation of the breast cancer screening programme.  But the women, when they're invited, should therefore be given a bit more information about the down sides, the harms, and more open discussion about the treatment options when something is found.

35:15 - Can food additives cause cancer?

Can food additives cause cancer?

Chris - That's a very good question and first of all, let's consider the question of what chemicals are in things because chemicals are in everything and it's worth bearing in mind that oxygen, a gas that we rely on to keep us alive actually also gives us cancer because when you breathe in oxygen, it can turn into a reactive form of oxygen in the body and that reactive form of oxygen can damage your DNA, and that in turn can lead to changes that make cells grow the way they shouldn't, and so, they can potentially become cancerous.

Everything that we actually depend on for our life is a chemical and lots of the things that we eat are complex chemicals mixed together. So just because there are lots of things in things doesn't necessarily mean that they're bad.

But your point is well-made in the sense that we have to be very sure about what we're eating and it is possible that many of the trappings of modern life, convenient foods, and also a poor choice of diet could definitely affect our health. I think probably the best thing to bear in mind is, what do the epidemiological studies - in other words, the studies of lots of members of the population who are eating a lot of different things - what do they show? And one very big study which is being done in our region by a group called EPIC who were looking at the east of England and they're asking, "What age do people get diseases at and die at, and what risk factors have they got?"

They found that if people didn't smoke, that they drank only in moderation, they took a bit of exercise, and this is the critical thing - they ate their 5-a-day fruit and vegetables, they could add up to 14 years onto the lifespan of the average individual. So in other words, what you put into your mouth does make a terribly big difference to your health outcome and fresh fruit and vegetables, not putting deleterious things like cigarettes in your mouth, and also, eating a healthy diet overall, and not too much alcohol (so don't make life boring, but don't go over the top), that's probably the best way and the best secret to have a healthy life.

37:49 - A Window on Spreading Cancer

Most deaths from cancer occur when the disease spreads – or metastasises - to other parts of the body. But we know very little about how this process physically happens. Now a team from...

A Window on Spreading Cancer
with Dr Jacco van Rheenen, Hubrecht Institute

Kat -   Most deaths from cancer occur when the disease spreads or metastasises to other parts of the body and we've already discussed about what might be going on at a molecular level, but we don't really know what's going on at a physical level.  What does it actually look like? 

Now, a team from Hubrecht Institute in the Netherlands have developed a technique to allow them to peer into organs within the body and watch metastasis taking place.  This gives us really important clues as to how it happens and potentially, a way to find drugs to stop it. 

We're joined by Dr. Jacco van Reenen.  He's one of the scientists behind the work.  Hello, Jacco.

Jacco -   Hello.

Kat -   So, tell me a bit about why you decided to do this.  Why can't we look at cancer spreading right now?

Jacco -   So, the big problem is that you would like to see which cells are growing out and not.  What we did before is, we took for example a biopsy or tissue sections and we just visualised on the microscope and we look through the cells.  That gives you just a snapshot, so you can for example see a thousand cells that arrive in the liver, but you have no idea which cells will grow into tumours or not.  Of course, you can also look at later stages and then you can see the tumours that grew out.  The problem there is that you have no idea which cells didn't make it and why they didn't make it.  So, what we now did is, we developed a technology where we labelled the tumour cells in mice and we could see on the microscopes how these tumour cells arrive in the liver and how they grow out into a full metastasis. 

Kat -   So this is real-time imaging of cancer spreading.  How does it work?  How can you actually see into a liver, you're doing this in mice I guess?

MetastasisJacco -   Yes.  So, you can just think of an airplane.  If you look through an airplane and you would like to see inside the airplane, you do not see anything because the light from within the airplane doesn't penetrate the wall of the airplane.  However, if you now go to the little windows of the airplane, you look through the glass, you'll certainly see exactly what's going on there.  We do exactly the same, so we invented a little window which is held in a titanium ring with a small piece of glass.  And it's very small, but we can implant into the belly of a mouse.  Through this little window, we can see what's going on inside this mouse, and we can start really to visualise the individual cells that arrive in the liver and how they grow out.

Kat -   So tell me about some of the things that you can see through these tiny, tiny windows on cancer.

Jacco -   So for example, what we observed is that the tumour cells that arrive, not every tumour cell is growing out, but what we observed at the ones that grew out, they leave the blood vessels and they migrate a little bit and then they start to grow.  What you would expect is that if a tumour cell starts to grow, you expect a little bowl of cells that is growing and growing, and growing.  But surprisingly, what we observed is that the cells that start to appear after a few rounds of multiplications is that the cells do not stick together.  They don't form a very dense little bowl, but they more form a larger bowl where the cell density is very low.  And then slowly over time, this tumour condenses slowly and if you then visualise over time, then you see the behaviours of the tumour cells in the different stages, in the early stages where the cells are not really connected to each other, they're very motile.  We found that if you block this motility, that this really blocks the growth of this tumour into a bigger tumour.

Kat -   So the key is actually the movement, not just the division or multiplication of the cells.

Jacco -   Well, we actually observed that these two things are connected.  So, if you are able to use drugs that block this movement of these cells, you also block the growth of these cells.  And we use drugs that, if we look through cell cultures, if we use this drug you can see that it stops.  They still proliferate.  If we now look in vivo, inside the mouse and we see at these very early stages and use the same drug, you can see that the cells stop moving, but they also stop proliferating, so it stop growing.

Kat -   What do you think these experiments could tell us about how cancer may be spreading in humans?  Do you have hope that these same drugs or developing these chemicals you're testing into drugs, could potentially stop cancer spreading in humans?

Jacco -   Well, I think the most important thing is that this is fundamental research, right?  So, we have many questions that we just would like to answer.  So how is a tumour cell growing to metastases?  Our research is just proof of principle, and we see now something new and whether it is holds true in humans, we have to do much more research of course [to find out].  We did just one type of cancer.  If you would really want to know what will help in the clinic, you have to find out whether this holds true in many types of cancer.  But of course, with this technique and now, our new technology, we have now the ability to really search for drugs that can block potential new drug targets that we could never really look or investigate before.

Kat -   And finally, how did it feel when you actually got this to work?

Jacco -   That was really amazing.  You just think about it all the time.  You really think about static images, so you think that that's a tumour cell and they're just growing, but you have no idea what's going on there.  And when I saw that for the first time, that you really see it moving, that you really can see how it's growing, of course, it was very exciting, but kind of terrifying as well because you realise that the mechanism that you see is causing the death of many people.  So, scientifically, I was very excited, but as just a human being, it was kind of terrifying as well.

43:18 - Triggering the immune system to attack tumours

Current cancer therapies often involve using drugs that are toxic to rapidly growing cells and this inevitably means that some healthy tissues get hit too. But if we could trigger our own...

Triggering the immune system to attack tumours
with Dr David Kirn, Jennerex Biotherapeutics, San Francisco

Current cancer therapies often involve using drugs that are toxic to rapidly growing cells and this inevitably means that some healthy tissues get hit also which causes side effects like hair loss, rashes, and organ damage.  But if we could trigger our own immune system to target a tumour, then we'd have a way to selectively combat the disease while simultaneously minimising the harm to other tissues.  The San Francisco based company Jennerex Biotherapeutics are using modified viruses to do this and with us to explain how is the company's Chief Medical Officer, Dr. David Kirn.  Hello, David.

David K. -   Hello.

Chris -   Please tell us how your approach works.

David K. -   Well, as you said, what we do is we get the body's own defence mechanism, the immune system, to turn its sights on cancer cells in the body and destroy them.  The way we do that is we engineer a virus that we call JX-594 to specifically target cancer cells, multiply in them and burst them, and at the same time produce many very potent danger signals to the immune response to get the body's immune system to turn on the cancer.

Chris -   So effectively, by making the virus infect the tumour and break open the tumour cells, because the immune system is seeing a virus infection and cancer cells, it doesn't only combat the virus infection.  It also combats the cancer.

Vaccinia virusDavid K. -   That's exactly right and then we have one other little trick that we use in JX-594 and that is to insert the gene for a very immune stimulatory protein into the virus, so virus-infected cancer cells will express this very potent cytokine that stimulates the immune system to recruit immune cells into the tumour to kill the tumour cell.  That cytokine is called GM-CSF and it's something that our body makes at low levels all the time, but now, with the JX-594 infection of cancers, they now express very high levels of GM-CSF, right in the tumour itself  to recruit the body's immune system into the tumour and activate it.

Chris -   So, when you apply the virus, do you inject it into one part of the tumour somewhere and then let it multiply?

David K. -   Well, it's an interesting thing about using virus therapy.  We can administer the product several different ways to cancer, so we can give it directly into the tumour, and one of the advantages of JX-594 which is a type of virus that is very stable in the blood, we can also give it IV.  So just through IV infusion into the arm as you might get a normal antibiotic and it's able to seek out tumours throughout the body and infect them, and lyse them.  So that's one of the interesting things about this approach.  We can use multiple methods of administration.

Chris -   What is the virus that you're using to do this?  I know you've given it obviously a research name because it's now modified organism, but what did it start out life as?

David K. -   Well, it started out as what's called a vaccinia virus.  So vaccinia virus is something that's very, very familiar to the medical community and to almost all of your listeners who are over the age of 40.  So, this is a virus that was used as a vaccine in children to eradicate small pox.  So it's not a small pox virus, but it tricks the body into protecting itself against small pox.  This is a virus that came from cow pox which was discovered by Edward Jenner in England over 200 years ago and led to the use of live viruses to vaccinate people against infectious diseases.  So, hundreds of millions of children throughout the world received live vaccinia virus as a childhood vaccine and that led to the eradication of small pox which is arguably one of mankind's greatest successes.

Chris -   The problem is, if people have had that small pox vaccination, does this not mean they will now be immune to vaccinia which means that if you come along and try and treat them when they've got a cancer with your therapy, it's not going to work.

David K. -   Yeah, that was a very important concern that we had.  We thought vaccinia was the ideal virus for this approach, but we were worried about that, so what we've done is studied in clinical trials whether pre-existing immunity to the vaccinia would prevent the effectiveness of the product.  Fortunately, because we use such high doses and the virus replicates to such high titres - high amounts in the tumour, we get very nice efficacy regardless of whether someone was vaccinated in the past as a child.

Chris -   One of the really attractive aspects of this is if you initiate the immune response in one part of the tumour then whether there are just single tumours or other tumours and metastases elsewhere in the body, they're going to get hit subsequently too by the immune response, but is this safe?

David K. -   Well, I think we had reason to believe it would be safe because the virus is very, very specific for cancers.  It only gets turned on in cancer cells that have these very common cancer pathways turned on and those are not turned on in normal cells.  So we don't see activation and multiplication of the virus in normal cells.  And then the body's immune system is very, very clever at determining foreign cells versus normal cells.  And so, we believed it was going to be safe and we've now treated roughly 200 patients with this therapy, and we've seen that to-date, it's been very, very safe.  We've not seen normal tissue damage or any sort of autoimmune problems with this therapy.

Chris -   I'm glad you brought up the issue of trials because what are those trials showing?  What sorts of cancers have you been able to treat with this and what are the outcomes?

David K. -   Well, as I said, we've treated about 200 patients to-date in phase 1 and phase 2 clinical trials, and we've treated a wide range of solid tumours including colon cancer, liver cancer, kidney, ovarian, melanoma, and others.  And what we've seen, as the virus does become activated in the cancer, it multiplies, it expresses this immune stimulatory cytokine called GM-CSF.  So it appears to be working in the way we thought it would in cancers and we've looked for effects on normal tissues and we've not seen those any safety issues with normal tissues, so it seems to be very, very cancer selective.  And then finally, most excitingly we've seen significant tumour destruction, tumour shrinkage in a number of patients and we do have randomised clinical trial data showing that at a high dose JX-594 actually improves the survival duration of patients with very advanced liver cancer.  So it's a very exciting time.  We're now moving into later stage, larger clinical trials that will be randomised to try to get the parts approved and on the market.

50:41 - What chemicals are used in Chemotherapy?

What chemicals are used in Chemotherapy?

David K. - Well, I think the original approach to systemic cancer treatment after radiation and surgery had failed was to use very toxic, poisonous drugs to try to get cancer cells to kill themselves. As you might imagine, this caused a lot of toxicity with the side effects that most people are very well aware of with chemotherapy and the products didn't work very well. I'd say, over the last 15 years, we've come up with much better and more specific ways of targeting cancers using very clever specific molecules that turn cancer's pathways and genes off. We've also come up with antibody therapy which is using antibodies which human make normally after infection and targeting these specifically to cancer cell markers on the surface of cancer cells. This has been a very effective way to target breast cancer with something called Herceptin and also, to turn off the blood supply to tumours with something called Avastin.

51:57 - What is brain cancer and can it be treated?

What is brain cancer and can it be treated?

David K. - Eventually, yes. Brain tumours can either be metastatic, spread from another spot from the body, or they can start in the brain. The ones that start in the brain that are the most difficult to treat are called glioblastoma multiforme.

A number of oncolytic viruses similar to the ones we're using are being tested in glioblastoma and eventually, we will test ours against glioblastoma as well, although we've not started these clinical trials yet.

52:32 - What is PSA, and what is it's connection to?

What is PSA, and what is it's connection to?

Kat - PSA is a molecule produced by prostate cells. There is a test: You can measure people's blood and see the level of PSA in it. This is called the PSA test. In some ways, it's a screening test for prostate cancer, but it's not part of the National Screening Programme for a number of reasons.

The big problem is that if your prostate starts growing, if it's got a cancer in it, then in many cases, it will produce lots and lots of PSA. So if a man has this test, and it shows that you have a very high PSA level, it's suggested that you might have a prostate cancer. But the problem is that at the moment - and this is what the problem with breast cancer screening is turning out to be - we can't tell which are the dangerous cancers; these dangerous prostate cancers that a man should definitely have treated. There are side effects of the treatment; it can leave men impotent, it can leave them incontinent. And we also can't tell which cancers will grow very slowly and cause no problems to a man in his lifetime. It's important to remember that most men in their 80s have some kind of prostate cancer, but it's not going to be the thing that kills them.

The other thing with the PSA test is that actually, some types of prostate cancer don't produce a lot of PSA. So, you'll miss men that do have prostate cancer because it won't pick them up.

So you could miss some dangerous cancers, and you could over-diagnose men that don't really have a prostate cancer that's going to kill them but could lead to them having unnecessary treatment, which is why it's a very difficult test to explain. There's a lot of information that doctors can give to men, deciding whether they want to have a PSA test and inform them about the options.

54:13 - Does angiogenesis benefit metastasis?

Does angiogenesis benefit metastasis?

Simon - Yes, angiogenesis is critical to metastasis. If you think about all the normal organs in our body, the brain, liver, lungs, they all have a blood supply that takes nutrients to those organs and gets rid of waste from the organs. A primary tumour is not normal, so it doesn't have a blood supply. And so, the only way it can spread around the body, metastasis as it were, is to actually develop a new blood supply. So tumours actually secrete factors, cytokines which encourage the growth of new blood vessels so that the primary tumour becomes vascularised so that tumour cells can now leak out into the blood stream and spread around the body. There are new anti-angiogenic treatment therapies undergoing treatment at the moment. One antibody which was mentioned earlier on is Avastin and also, small inhibitors of enzymes called vegf receptors and these are currently being tested in clinical trials at the moment. So, anti-angiogenic therapy is very much a topical area.

55:44 - Why do fungi make hallucinogens?

Why do some fungi produce hallucinogenic chemicals? How do such trippy chemicals benefit the fungi?

Why do fungi make hallucinogens?

We put this to Professor Mike Cole from Anglia Ruskin University...

Mike - The reason that many fungi produce what are called secondary metabolites is as a defence reaction to their environment. For example, they might prevent attack by animals, plants, other fungi, or in fact, bacteria. They're called secondary metabolites because they're not essential for life in the same way that vitamins, sugars and amino acids are, but they do confer some advantage on, in this case, the fungus that produces them.

The cost includes producing precursor chemicals, supplying the energy compounds, supplying the reducing power. Whilst as forensic scientists we understand a lot about the genetics for the identification of these organisms, there is nothing known about the genetics of how these compounds are produced although we do understand the biochemical pathway in terms of the starting materials and the end product.

There are a host of other compounds that are produced by fungi, plants and bacteria. Perhaps one of the most famous of these are the ergotamine alkaloids which are used postoperatively, but also are hallucinogenic. And also, compounds produced by fungus called claviceps which supplies the precursor chemical for our friend, LSD.

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