Outsourcing the Immune Response

We’re very trendy in these pages, for no other reason than that the idea is to keep up to date with exciting events in cancer biology. Accordingly, we have recently talked quite a lot about the emerging field of cancer immunotherapy – the notion that our in-built immune system will try to kill cancer cells as they emerge, because it ‘sees’ them as being to some extent ‘foreign’, but that when tumours make their presence known it has not been able to do the job completely. The idea of immunotherapy is to give our in-house system a helping hand and we’ve seen some of the approaches in Self Help – Part 2 and Gosh! Wonderful GOSH.

The immune see-saw

Our immune system walks a tight-rope: on the one hand it should attack and eliminate any ‘foreign’ cells it sees (so that we aren’t killed by infections) but, on the other, if it’s too efficient it will start destroying out own cells (which is what happens in auto-immune diseases such as Graves disease (overactive thyroid gland) and rheumatoid arthritis.

Like much of our biology, then, it’s a tug-of-war: to kill or to ignore? And, like the cell cycle that determines whether a cell should grow and divide to make two cells, it’s controlled by the balance between ‘accelerators’ and ‘brakes’. The main targets for anti-tumour immune activity are mutated proteins that appear on the surface of cancer cells – called neo-antigens (see The Shape of Things to Come?)

The aim of immunotherapy then is to boost tumour responses by disabling the ‘brakes’. And it’s had some startling successes with patients going into long-term remission. So the basic idea works but there’s a problem: generally immunotherapy doesn’t work and, so far, in only about one in ten of patients have there been significant effects.

Sub-contracting to soup-up detection

Until now it’s seemed that only a very small fraction of expressed neo-antigens (less than 1%) can turn on an immune response in cancer patients. In an exciting new take on this problem, a team of researchers from the universities of Oslo and Copenhagen have asked: “if someone’s immune cells aren’t up to recognizing and fighting their tumours (i.e. ‘seeing’ neo-antigens), could someone else’s help?” It turns out that many more than 1 in 100 neo-antigens are able to cause an immune response. Even more exciting (and surprising), immune cells (T cells) from healthy donors can react to these neo-antigens and, in vitro at least (i.e. in cells grown in the laboratory), can kill tumour cells.

118. pic

Genetic modification of blood lymphocytes

T cells are isolated from a blood sample and novel genes inserted into their DNA. The engineered T cells are expanded and then infused into the patient. In the latest development T cells from healthy donors are screened for reactivity against neo-antigens expressed in a patient’s melanoma. T cell receptors that  recognise neo-antigens are sequenced and then transferred to the patient’s T cells.

How does that work?

T cells (lymphocytes) circulating in the blood act, in effect, as scouts, scanning the surface of all cells, including cancer cells, for the presence of any protein fragments on their surface that should not be there. The first contact with such foreign protein fragments switches on a process called priming that ultimately enables T cells to kill the aberrant cells (see Invisible Army Rouses Home Guard).

What the Scandinavian group did was to screen healthy individuals for tissue compatibility with a group of cancer patients. They then identified a set of 57 neo-antigens from three melanoma patients and showed that 11 of the 57 could stimulate responses in T cells from the healthy donors (T cells from the patients only reacted to two neo-antigens). Indeed the neo-antigen-specific T cells from healthy donors could kill melanoma cells carrying the corresponding mutated protein.

What can possibly go wrong?

The obvious question is, of course, how come cells from healthy folk have a broader reactivity to neo-antigens than do the cells of melanoma patients? The answer isn’t clear but presumably either cancers can make T cell priming inefficient or T cells become tolerant to tumours (i.e. they see them as ‘self’ rather than ‘non-self’).

And the future?

The more critical question is whether the problem can be short-circuited and Erlend Strønen and friends set about this by showing that T cell receptors in donor cells that recognize neo-antigens can be sequenced and expressed in the T cells of patients. This offers the possibility of a further type of adoptive cell transfer immunotherapy to the one we described in Gosh! Wonderful GOSH.

https://cancerforall.wordpress.com/2015/11/19/gosh-wonderful-gosh/

As one of the authors, Ton Schumacher, put it “Our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens. The receptor that is used by these donor T-cells can then be used to genetically modify the patient’s own T cells so these will be able to detect the cancer cells.”

And Johanna Olweus commented that “Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput. We are currently exploring high-throughput methods to identify the neo-antigens that the T cells can “see” on the cancer and isolate the responding cells. But the results showing that we can obtain cancer-specific immunity from the blood of healthy individuals are already very promising.”

References

Strønen, M. Toebes, S. Kelderman, M. M. van Buuren, W. Yang, N. van Rooij, M. Donia, M.-L. Boschen, F. Lund-Johansen, J. Olweus, T. N. Schumacher. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science, 2016.

“Fighting cancer with the help of someone else’s immune cells.” ScienceDaily. ScienceDaily, 19 May 2016.

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The Shape of Things to Come?

One of the problems of trying to keep up with cancer – and indeed helping others to do so – is that you (i.e. ‘I’) get really irritated with the gentlemen and ladies of the press for going over the top in their efforts to cover science. I have therefore been forced to have a few rants about this in the past – actually, when I came to take stock, even I was a bit shocked at how many. Heading the field were Not Another Great Cancer Breakthough, Put A Cap On It and Gentlemen… For Goodness Sake. And not all of these were provoked by The Daily Telegraph!

If any of the responsible reporters read this blog they probably write me off as auditioning for the Grumpy Old Men tv series. But at least one authoritative voice says I’m really very sane and balanced (OK, it’s mine). Evidence? The other day I spotted the dreaded G word (groundbreaking) closely juxtaposed to poor old Achilles’ heel – and yes, it was in the Telegraph – but, when I got round to reading the paper, I had to admit that the work referred to was pretty stunning. Although, let’s be clear, such verbiage should still be banned.

A Tumour Tour de Force

The paper concerned was published in the leading journal Science by Nicholas McGranahan, Charles Swanton and colleagues from University College London and Cancer Research UK. It described a remarkable concentration of current molecular fire-power to dissect the fine detail of what’s going on in solid tumours. They focused on lung cancers and the key steps used to paint the picture were as follows:

1. DNA sequencing to identify mutations that produced new proteins in tumour cells (called tumour-associated antigens or ‘neoantigens’ – meaning molecular flags on the cell surface that can provoke an immune response – i.e. the host makes antibody proteins that react with (stick to) the antigens). Typically they found just over 300 of these ‘neoantigens’ per tumour – a reflection of the genetic mayhem that occurs in cancer.

2 tumoursVariation in neoantigen profile between two multi-region sequenced non-small cell lung tumours. There were approximately 400 (left) and 300 (right) neoantigens/tumour

  • Blue: proportion of clonal neoantigens found in every tumour region.
  • Yellow: subclonal neoantigens shared in multiple but not all tumour regions.
  • Red: subclonal (‘private’) neoantigens found in only one tumour region.
  • The left hand tumour (mostly blue, thus highly clonal) responded well to immunotherapy (from McGranahan et al. 2016).

2. Screening the set of genes that regulate the immune system – that is, make proteins that detect which cells belong to our body and which are ‘foreign.’ This is the human leukocyte antigen (HLA) system that is used to match donors for transplants – called HLA typing.

3. Isolating specialised immune cells (T lymphocytes) from samples of two patients with lung cancer, growing them in the lab to expand the population and testing how good these tumour-infiltrating cells were at recognizing the abnormal proteins (neo-antigens) on cancer cells.

4. Detecting proteins released by different types of infiltrating T cells that regulate the immune response. These include so-called immune checkpoint molecules that limit the extent of the immune response. This showed that T cell subsets that were very good at recognizing neo-antigens – and thus killing cancer cells (they’re CD8+ T cells or ‘killer’ T cells) also made high levels of proteins that restrain the immune response (e.g., PD-1).

5. Showing that immunotherapy (using the antibody pembrolizumab that reacts with PD-1) could significantly extend survival of patients with advanced non-small cell lung cancer. We’ve already met this approach in Self-help Part 1.

The critical finding was that the complexity of the tumour (called the clonal architecture) determines the outcome. Durable benefit from this immunotherapy requires a high level of mutation but a restricted range of neo-antigens. Put another way, tumours that are highly clonal respond best because they have common molecular flags present on every tumour cell.

6. Using the same methods on some skin cancers (melanomas) with similar results.

What did this astonishing assembly of results tell us?

It’s the most detailed picture yet of what’s going on in individual cancers. As one of the authors, Charles Swanton, remarked “This is exciting. This opens up a way to look at individual patients’ tumours and profile all the antigen variations to figure out the best ways for treatments to work. This takes personalised medicine to its absolute limit where each patient would have a unique, bespoke treatment.”

He might have added that it’s going to take a bit of time and a lot of money. But as a demonstration of 21st century medical science it’s an absolute cracker!

References

McGranahan et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 10.1126/science.aaf490 (2016).

 

Guess Who’s Coming to Dinner?

 

Question: when is a gene not a gene? Answer: when it’s a pseudogene.

Genes are familiar enough these days when the acronym DNA has become part of everyday speech “It is in Toyota’s DNA that mistakes made once will not be repeated”, as the CEO of Toyota rather sinisterly remarked. You could say that’s pseudo-scientific rubbish but, despite that kind of liberty-taking, most will know that a gene is a stretch of our genetic material (DNA) that carries the code to make a closely related RNA molecule that, in turn, may be used as a template to make a protein ­– it’s the molecular unit of heredity. Well known too is that the Greeks gave us ‘pseudo’ – but what’s a ‘lying’ or ‘false’ gene – and who cares?

No prizes for guessing that we should all be interested because it’s emerging that pseudogenes can be important players in cancer.

Player’s biography

Pseudogenes are somewhat disreputable because they are relatives of normal genes that along the evolutionary highway have become dysfunctional by losing the capacity to be ‘expressed’ – that is, their code can no longer be transformed into RNA and protein. You could think of them as an example of the shambolic way in which species have evolved by random happenstance so that they work in their own particular niches. And if you want the outstanding example of unintelligent design, look no further than yourself, as we did in Holiday Reading (2), Poking the Blancmange.

Just for background, although it doesn’t affect the main story, there are three ways in which our genome can acquire a pseudogene:

1. A normal gene becomes functionally extinct: odd mutational events disable the stretches of DNA that control its expression. The gene is like a siding on a railway that isn’t used for years and years until eventually the points  seize up (it would be a ‘switch’ on US railroads) and the cell machinery can no longer get at it – but when this does happen we get by without that gene.

2. During evolution genes quite often get duplicated – giving multiple copies: if one of these loses its regulatory bits the duplicate gene is switched off – it’s become a ghost.

3. We owe about 8% of our genome to viruses – mainly those with RNA genomes (retroviruses) whose life-cycle turns their RNA into DNA that has then been stuck into our genome. And that’s a lot (about 100,000 bits of retrovirus DNA) especially bearing in mind that only about 1% of our genome encodes proteins.

So our precious genome is littered with corpses and fragments thereof. In the past there’s been a regrettable tendency to label this material as ‘junk’ but increasingly we’re now discovering that there may be genetic life after death, so to speak. It’s not surprising if you think about it. If random events can inactivate a gene then they might do the reverse, even if that may be a much rarer event. And indeed it’s now clear that pseudogenes can be brought back to life through the random mutational events that characterise the rough and tumble of cellular life.

So not all pseudogenes are extinct then?

Correct. Obviously we wouldn’t be wittering on about them had not some bright sparks just shown that pseudogenes – or at least one in particular – can be re-awakened to play a part in cancer. The luminaries are Florian Karreth, Pier Paolo Pandolfi and friends from all over the place (USA, UK, Italy, Singapore) who found that a pseudogene called BRAFP1 (a relative of the normal BRAF gene) can help to drive cancer development. Some earlier studies had shown that BRAFP1 was expressed (i.e. RNA was made from DNA) in various human tumours but Karreth & Co extended this, detecting significant levels of the pseudogene RNA in lymphomas and thyroid tumours and also in cells from melanoma, prostate cancer and lung cancer, whilst it’s not switched on in the corresponding normal cells.

To show that this pseudogene can drive cancers they genetically engineered its over-expression in mice, whereupon the animals developed an aggressive malignancy akin to human lymphoma (specifically diffuse large B cell lymphoma). Short-circuiting an enormous amount of work, it emerged that the pseudogene up-regulated a signaling pathway involving its normal counterpart, BRAF, that drives proliferation.

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How a pseudogene (BRAFP1) might drive cancer. Top: The scheme illustrates the ‘central dogma’ of molecular biology: DNA makes RNA makes protein. In normal cells a family of micro RNAs (different coloured wiggles) regulate the level of BRAF RNA and hence of BRAF protein (above white line).  Bottom: When the pseudogene BRAFP1 is switched on its RNA competes for the negative regulators: the result is more BRAF RNA making more BRAF protein – making cancer (Karreth et al., 2015).

Interfering RNA

The pseudogene’s RNA manages to interfere with normal control by targeting another type of RNA – micro RNAs, so called because they’re very short (about 20 bases (units) long – so they’re encoded by tiny stretches of the over 3,000 million units that make up the genome). Small they may be but there are hundreds of them and it’s become clear over the last few years that they play critical roles in regulating how much protein is made from specific RNAs. Their method is simple: they recognize (i.e. bind to) stretches of RNA that encode proteins, thereby blocking translation into protein.

Karreth & Co showed that there are about 40 different micro RNAs that can stick to the RNAs encoding BRAF or BRAFP1. Normally when there’s no (or very little) BRAFP1 around they have only BRAF to act on – and their role is to control the proliferation signal it transmits – i.e. to keep that signal to what’s required for normal cell growth control. BUT, when the pseudogene RNA is made in significant amounts the attentions of the 40 micro RNAs are divided. Result: more BRAF RNA, more BRAF protein, higher cell proliferation.

It’s a bit like you’re just sitting down to a family dinner for four when there’s a knock on the door and in walks long lost Uncle Bert, complete with wife and two kids in tow. Of course you invite them to dine too – but now a meal for four has to stretch to eight. There is something for everybody – just not as much. Similarly for the regulators of BRAF: when BRAFP1 is present there’s half as much of the RNA regulators for each – and the result, bearing mind that they are negative regulators, is that the activity of BRAF goes up and the cells proliferate more avidly. The pseudogene is driving cancer.

First but not last

For decades pseudogenes were thought of as ‘junk’ DNA along with most of the rest of the genome that didn’t encode proteins – though I might say that was a concept I never promoted. Beware labeling anything in our genome as junk for it may rise, Kraken like, to remind us of our ignorance. And, now that one pseudogene has come in from the cold and been shown to drive some cancers, you can be confident that others will follow.

References

Karreth, F.A. et al. (2015). The BRAF Pseudogene Functions as a Competitive Endogenous RNA and Induces Lymphoma In Vivo. Cell 161, 319–332.

Blowing Up Cancer

To adapt the saying of the sometime British Prime Minister Harold Wilson, a month is a long time in cancer research. {I know, you’ve forgotten – as well you might. He was PM from 1964 to 1970 and again from 1974 to 1976. His actual words were “A week is a long time in politics”}. When I started to write the foregoing Self Helps (Parts 1 & 2) I had absolutely no intention of mentioning the subject of today’s sermon – viral immunotherapy. But how times change and a recent report has hit the headlines – so here goes.

The reason for my reticence is that this is not a new field – far from it. Folk have been trying to target tumour cells with active viruses for twenty years but efforts have foundered to the extent that the new report is the first time in the western world that a phase III trial (when a drug or treatment is first tested on large groups of people) of cancer “virotherapy” has definitively shown benefit for patients with cancer, although a virus (H101) made by the Shanghai Sunway Biotech Co. was licensed in China in 2005 for the treatment of a range of cancers.

Hard bit already done

I appreciate that getting the hang of immunotherapy in the two Self Helps wasn’t a total doddle – but it was worth it, wasn’t it, bearing in mind we’re dealing with life and death here. My friend and correspondent Rachel Bown had to resort to her GCSE biology notes (since she met me I think she keeps them on the coffee table) but is now up to speed.

Fortunately this bit is pretty easy to follow – it’s just an extension of the viral jiggery-pokery we met in Self Help Part 2. There we saw that using ‘disabled’ viruses is a neat way of getting new genetic material into cells. The viruses have key bits of their genome (genetic material) knocked out – so they don’t have any nasty effects and don’t replicate (make more of themselves) once inside cells. Inserting new bits of DNA carrying a therapeutic gene turns them into a molecular delivery service.

Going viral

In virotherapy there’s one extra wrinkle: the viruses, though ‘disabled’, still retain the capacity to replicate – and this has two effects. First, more and more virus particles (virions) are made in an infected cell until eventually it can hold no more and it bursts. The cell is done for – but a secondary effect is that the newly-made virions spill out and drift off to infect other cells. This amplifies the effect of the initial injection of virus and, in principle, will continue as long as there are cells to infect.

A new tool

The virus used is herpes simplex (HSV-1) of the relatively harmless type that causes cold sores and, increasingly frequently, genital herpes. The reason for this choice is that sometimes, not very often, science gets lucky and Mother Nature comes up with a helping hand. For HSV-1 it was the completely unexpected discovery that when you knock out one of its genes the virus becomes much more effective at replicating in tumour cells than in normal cells. That’s a megagalactic plus because, in effect, it means the virus targets tumour cells, thereby overcoming one of the great barriers to cancer therapy. In this study another viral gene was also deleted, which increases the immune response against infected tumour cells.

All this cutting and pasting (aka genetic engineering) is explained in entertaining detail in Betrayed by Nature but for now all that matters is that you end up with a virus that:

  1. Gets into tumour cells much more efficiently than into normal cells,
  2. Makes the protein encoded by the therapeutic gene, and
  3. Replicates in the cells that take it up until eventually they are so full of new viruses they go pop.

The finished product, if you can get your tongue round it, goes by the name of talimogene laherparepvec, mercifully shortened by the authors to T-VEC (made by Amgen). So T-VEC mounts a two-pronged attack – what the military would call a pincer movement. Infected tumour cells are killed (they’re ‘lysed’ by viral overload) and the inserted gene makes a protein that soups up the immune response – called GM-CSF (granulocyte macrophage colony-stimulating factor). The name doesn’t matter: what’s important is that it’s a human signaling molecule that stimulates the immune system, the overall result being production of tumour-specific T cells.

Fig. 1 Viral Therapy

Virotherapy. Model of a virus (top). The knobs represent proteins that enable the virus to stick to cells. Below: sequence of injecting viruses that are taken up by tumour cells that eventually burst to release new virions that diffuse to infect other tumour cells.

And the results?

The phase III trial, led by Robert Andtbacka, Howard Kaufman and colleagues from Rutgers Cancer Institute of New Jersey, involved 64 research centres worldwide and 436 patients with aggressive, inoperable malignant melanoma who received either an injection of T-VEC or a control immunotherapy. Just over 16% of the T-VEC group showed a durable response of more than six months, compared with 2% given the control treatment. About 10% of the patients treated had “complete remission”, with no detectable cancer remaining – considered a cure if the patient is still cancer-free five years after diagnosis.

Maybe this time?

We started with Harold Wilson and it was in between his two spells in Number 10 that President Nixon declared his celebrated ‘War on Cancer’, aimed at bringing the major forms of the disease under control within a decade or two. It didn’t happen, as we might have guessed. Back in 1957 in The Black Cloud the astrophysicist Sir Fred Hoyle has the line ‘I cannot understand what makes scientists tick. They are always wrong and they always go on.’ To be fair, it was a science fiction novel and the statement clearly is only partly true. But it’s not far off and in cancer there’s been rather few of the media’s beloved ‘breakthroughs’ and a great deal of random shuffling together with, overall, some progress in specific areas. Along the bumpy highway there have, of course, been moments of high excitement when some development or other has briefly looked like the answer to a maiden’s prayer. But with time all of these have fallen, if not by the wayside, at least into their due place as yet another small step for man. The nearest to a “giant leap for mankind” has probably been coming up with the means to sequence DNA on an industrial scale that is now having a massive impact on the cancer game.

When Liza Minnelli (as Sally Bowles in Cabaret) sings Maybe this time your heart goes out to the poor thing, though your head knows it’ll all end in tears. But this time, maybe, just maybe, the advent of cancer immunotherapy in its various forms will turn out to be a new era. Let us fervently hope so but, even if it does, the results of this Phase III trial show that a long struggle lies ahead before treatments arrive that have most patients responding.

We began Self Help – Part 1 with the wonderful William Coley and there’s no better way to pause in this story than with his words – reminding us of a bygone age when the scientist’s hand could brandish an artistic pen and space-saving editors hadn’t been invented:

“While the results have not been as satisfactory as one who is seeking perfection could wish, … when it comes to the consideration of a new method of treatment for malignant tumours, we must not wonder that a profession with memories overburdened with a thousand and one much-vaunted remedies that have been tried and failed takes little interest in any new method and shows less inclination to examine into its merits. Cold indifference is all it can expect, and rightly too, until it has something beside novelty to offer in its favour.”

References

Mohr, I. and Gluzman, Y. (1996). A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. The EMBO Journal 15, 4759–66.

Andtbacka, R.H.I. et al. (2015). Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. 10.1200/JCO.2014.58.3377

The Hay Festival

According to the Hay Festival  a recording of my talk ‘Demystifying Cancer’ on Wednesday 28th May should be available on their web site shortly and it can also be heard on the university site. However, I thought it might be helpful to post a version, not least for the for the rather breathless lady who arrived at the book signing session apologising for missing the lecture because she’d got stuck in mud. So for her and perhaps for many others I had the privilege of chatting to afterwards, read on …

 The Amazing World of Cells, Molecules … and CancerOpening pic

One of the biggest influences on my early years was the composer and conductor Antony Hopkins, who died a few days ago. Most of what I knew about music by the time I was 15 came from his wonderfully clear dissections of compositions in the series Talking About Music broadcast by the BBC Third Programme. When he was axed by the Beeb in 1992 for being ‘too elitist’ – yes, they talked that sort of drivel even then – Hopkins might have wished he’d been a biologist. After all, biology must be the easiest subject in the world to talk about. Your audience is hooked from the outset because they know it’s about them – if not directly then because all living things on the planet are interlinked – so even the BBC would struggle to make an ‘elitism’ charge stick. They know too that it’s beautiful, astonishing and often funny – both from what they see around them and also, of course, courtesy of David Attenborough. So it’s not a surprise when you show them that the micro-world of cells and molecules is every bit as wonderful.

The secret of life

What does come as a bit of a shock to most non-scientists is when you explain the secret of life. No, that’s not handing round pots of an immortalization elixir – much better, it’s outlining what’s sometimes rather ponderously called the central dogma of molecular biology – the fact that our genetic material (aka DNA) is made from only four basic units (most easily remembered by their initials: A, C, G and T – humans have over three thousand million of these stuck together). This is our ‘genome’ and the ‘genetic code’ enshrined in the DNA sequence makes us what we are – with small variations giving rise to the differences between individuals. The genetic code carries instructions for glueing together another set of small chemicals to make proteins. There are 20 of these (amino acids) and they can be assembled in any order to make proteins that can be thousands or even tens of thousands of amino acids long. These assemblies fold up into 3D shapes that give them specific activities. Proteins make living things what they are – they’re ‘the machines of life’ – and their infinite variety is responsible for all the different species to have appeared on earth. Can the basis of life really be so simple?

The paradox of cancer

Turning to cancer, a three word definition of ‘cells behaving badly’ would do fine. A more scientific version would be ‘cells proliferating abnormally.’ That is, cells reproducing either when they shouldn’t, or more rapidly than normal, or doing so in the wrong place. The cause of this unfriendly behavior is damaged DNA, that is, alteration in the genetic code – any such change being a ‘mutation’. If a mutation affects a protein so that it becomes, say, hyperactive at making cells proliferate (i.e. dividing to make more cells), you have a potential cancer ‘driver’. So at heart cancer’s very simple: it’s driven by mutations in DNA that affect proteins controlling proliferation. That’s true even of the 20% or so of cancers caused by chronic infection – because that provokes inflammation, which in turn leads to DNA damage.

The complexity of cancer arises because, in contrast to several thousand other genetic diseases in which just a single gene is abnormal (e.g., cystic fibrosis), tumour cells accumulate lots of mutations. Within this genetic mayhem, relatively small groups of potent mutations (half a dozen or so) emerge that do the ‘driving’. Though only a few ‘driver mutations’ are required, an almost limitless number of combinations can arise.

Accumulating mutations takes time, which is why cancers are predominantly diseases of old age. Even so, we should be aware that life is a game of genetic roulette in which each individual has to deal with the dice thrown by their parents. The genetic cards we’re dealt at birth may combine with mutations that we pick up all the time (due to radiation from the sun and the ground, from some foods and as a result of chemical reactions going on inside us) to cause cancers and, albeit rarely, in unlucky individuals these can arise at an early age. However, aside from what Mother Nature endows, humans are prone to giving things a helping hand through self-destructive life-style choices – the major culprits, of course, being tobacco, alcohol and poor diets, the latter being linked to becoming overweight and obese. Despite these appalling habits we’re living longer (twice as long as at the beginning of the twentieth century) which means that cancer incidence will inevitably rise as we have more time to pick up the necessary mutations. Nevertheless, if we could ban cigarettes, drastically reduce alcohol consumption and eat sensibly we could reduce the incidence of cancers by well over a half.

How are we doing?

Some readers may recall that forty-odd years ago in 1971 President Nixon famously committed the intellectual and technological might of the USA to a ‘War on Cancer’ saying, in effect, let’s give the boffins pots of money to sort it out pronto. Amazing discoveries and improved treatments have emerged in the wake of that dramatic challenge (not all from Uncle Sam, by the way!) but, had we used the first grant money to make a time machine from which we were able to report back that in 2013 nearly six hundred thousand Americans died from cancer, that the global death toll was over eight million people a year and will rise to more than 13 million by 2030 (according to the Union for International Cancer Control), rather less cash might subsequently have been doled out. Don’t get me wrong: Tricky Dicky was spot on to do what he did and scientists are wonderful – clever, dedicated, incredibly hard-working, totally uninterested in personal gain and almost always handsome and charming. But the point here is that, well, sometimes scientific questions are a little bit more difficult than they look.

Notwithstanding, there have been fantastic advances. The five year survival rates for breast and prostate cancers have gone from below 50% to around 90% – improvements to which many factors have contributed including greater public awareness (increasing the take-up of screening services), improved surgical and radiology methods and, of course, new drugs. But for all the inspiration, perspiration and fiscal lubrication, cancer still kills over one third of all people in what we like to refer to as the “developed” world, globally breast cancer killed over half a million in 2012 and for many types of cancer almost no impact has been made on the survival figures. In the light of that rather gloomy summary we might ask whether there is any light at the end of the tunnel.

The Greatest Revolution

From one perspective it’s surprising we’ve made much progress at all because until just a few years ago we had little idea about the molecular events that drive cancers and most of the advances in drug treatment have come about empirically, as the scientists say – in plain language by trial and error. But in 2003 there occurred one of the great moments in science – arguably the most influential event in the entire history of medical science – the unveiling of the first complete DNA sequence of a human genome. This was the product of a miraculous feat of international collaboration called The Human Genome Project that determined the order of the four units (A, C, G and T) that make up human DNA (i.e. the sequence). Set up in 1990, the project was completed by 2003, two years ahead of schedule and under budget.

If the human genome project was one of the most sensational triumphs in the history of science what has happened in the ensuing 10 years is perhaps even more dazzling. Quite breathtaking technical advances now mean that DNA can be sequenced on a truly industrial scale and it is possible to obtain the complete sequence of a human genome in a day or so at a cost of about $1,000.

These developments represent the greatest revolution because they are already having an impact on every facet of biological science: food production, microbiology and pesticides, biofuels – and medicine. But no field has been more dramatically affected by this technological broadside than cancer and already thousands of genomes have been sequenced from a wide range of tumours. The most striking result has been to reveal the full detail of the astonishing genetic mayhem that characterizes cancer cells. Tens of thousands or even hundreds of thousands of mutations featuring every kind of molecular gymnastics imaginable occur in a typical tumour cell, creating a landscape of stunning complexity. At first sight this makes the therapeutic challenge seem daunting, but all may not be lost because the vast majority of this genetic damage plays no role in cancer development (they’re ‘passenger’ mutations) and the power of sequencing now means they can be sifted from the much smaller hand of ‘driver’ mutations. From this distillation have emerged sets of ‘mutational signatures’ for most of the major types of cancers. This is a seismic shift from the traditional method of assessing tumours – looking directly at the cells after treating them with markers to highlight particular features – and this genetic approach, providing for the first time a rigorous molecular basis for classifying tumours, is already affecting clinical practice through its prognostic potential and informing decisions about treatment.

A new era

One of the first applications of genomics to cancer, was undertaken by a group at The Wellcome Trust Sanger Institute near Cambridge (where the UK part of the Human Genome Project had been carried out), who screened samples of the skin cancer known as malignant melanoma. This is now the fifth most common UK cancer – in young people (aged 15 to 34) it’s the second most common – and it killed over 2,200 in 2012. Remarkably, about half the tumours were found to have a hyperactivating mutation in a gene called BRAF, the effect being to switch on a signal pathway so that it drives cell proliferation continuously. It was a remarkable finding because up until then virtually nothing was known about the molecular biology of this cancer. Even more amazingly, within a few years it had lead to the development of drugs that caused substantial regression of melanomas that had spread to secondary sites (metastasized).

This was an early example of what has become known as personalized medicine – the concept that molecular analysis will permit treatment regimens to be tailored to the stage of development of an individual’s cancer. And maybe, at some distant time, the era of personalized medicine will truly come about. At the moment, however, we have very few drugs that are specific for cancer cells – and even when drugs work initially, patients almost invariably relapse as tumours become resistant and the cancer returns – one of the major challenges for cancer biology.

It behoves us therefore to think laterally, of impersonal medicine if you like, and one alternative approach to trying to hit the almost limitless range of targets revealed by genomics is to ask: do tumour cells have a molecular jugular – a master regulator through which all the signals telling it to proliferate have to pass. There’s an obvious candidate – a protein called MYC that is essential for cells to proliferate. The problem with stopping MYC working is that humans make about one million new cells a second, just to maintain the status quo – so informed opinion says that blocking MYC will kill so many cells the animal will die – which would certainly fix cancer but not quite in the way we’re aiming for. Astoundingly, it turns out in mice at least it doesn’t work like that. Normal cells tolerate attenuation of MYC activity pretty well but the tumour cells die. What a result!! We should, of course, bear in mind that the highway of cancer therapy is littered with successful mouse treatments that simply didn’t work in us – but maybe this time we’ll get lucky.

An Achilles’ heel?

In defining cancers we noted the possibility that tumour cells might proliferate in the wrong place. So important is this capacity that most cancer patients die as a result of tumour cells spreading around the body and founding secondary colonies at new sites – a phenomenon called metastasis. Well over 100 years ago a clever London physician by the name of Stephen Paget drew a parallel between the growth of tumours and plants: ‘When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.’ From this emerged the “seed and soil” theory as at least a step to explaining metastasis. Thus have things languished until very recent findings have begun to lift the metastatic veil. Quite unexpectedly, in mouse models, primary tumours dispatch chemical messengers into the blood stream long before any of their cells set sail. These protein news-bearers essentially tag a landing site within the circulatory system on which the tumour cells touch down. Which sites are tagged depends on the type of tumour – consistent with the fact that human cancers show different preferences in metastatic targets.

These revelations have been matched by stunning new video methods that permit tumour cells to be tracked inside live mice. For the first time this has shone a light on the mystery of how tumour cells get into the circulation – the first step in metastasis. Astonishingly tumour cells attach themselves to a type of normal cell, macrophages, whose usual job is to engulf and digest cellular debris and bugs. The upshot of this embrace is that the macrophages cause the cells that line blood vessels to lose contact with each other, creating gaps in the vessel wall through which tumour cells squeeze to make their escape. This extraordinary hijacking has prognostic value and is being used to develop a test for the risk of metastasis in breast cancers.

The very fact that cancers manifest their most devastating effects by spreading to other sites may lay bare an Achilles’ heel. Other remarkable technical developments mean that it’s now possible to fish out cancer cells (or DNA they’ve released) from a teaspoonful of circulating blood (that’s a pretty neat trick in itself, given we’re talking about fewer than 100 tumour cells in a sea of several billion cells for every cubic millimeter of blood). Coupling this to genome sequencing has already permitted the response of patients to drug therapy to be monitored but an even more exciting prospect is that through these methods we may be moving towards cancer detection perhaps years earlier than is possible by current techniques.

As we’ve seen, practically every aspect of cancer biology is now dominated by genomics. Last picIt’s so trendy that anyone can join in. Songs have been written about DNA and you can even make a musical of your own genetic code, French physicist Joel Sternheimer having come up with a new genre – protein music – in which sequence information is converted to musical notes. Antony Hopkins, ever receptive to new ideas, would have been enthralled and, with characteristic enthusiasm, been only too happy to devote an episode of Talking About Music to making tunes from nature.

What Took You So Long?

A long, long time ago – 25 years to be precise – I was lucky enough to work for a few months at The University of New England in Armidale, up on the Northern Tablelands of New South Wales. And jolly wonderful it was too. You could see grazing kangaroos from my lab window and I got to play grade cricket! To anyone who’ll listen I can still describe in vivid detail the scoring of my first run in Oz. We’d won the toss and … (that’s quite enough cricket, Ed).

Equally wonderful is the fact that, in part courtesy of The University of Queensland, I’m going again to Oz – this time to do what I didn’t manage then: visit all the major cities. We begin in Brisbane this week giving a lecture in the U of Q’s Global Leadership series (yes really!), explaining the biology of cancer to an audience of largely non-scientists – at least I hope I’ve got the right brief! We end up in Perth in May having, in between if I can stick the pace, given a variety of talks and seminars to the general public, to schools and to cancer research institutes in Sydney, Melbourne and Adelaide. How good is that? Being invited to warble on about one of your favorite subjects whilst touring Oz? Wow!

What’s new?

All of which makes you think a bit about Father Time and what has happened in the interim. Answer quite a lot, of course. Collapse of communism, collapse and resurgence of Australian cricket (that’s your last warning, Ed) and so on but we’re supposed to inform and enthuse about cancer here so how’s that faired, particularly in Australia? Well, in the year I first followed Captain Cook (watch it, Ed) onto the shore of Botany Bay about 60,000 Australians were diagnosed with cancers of one sort or another and some 30,000 died from these diseases. At that time one in three men and one in four women would be directly affected by cancer in the first 75 years of life.

A Cook

Alastair Cook

And now? This time round the estimated numbers are 128,000 and over 43,000 with one in two men/one in three women discovering they have cancer by time they’re 85. All told, cancer accounts for about three in ten Australian deaths – much the same contribution as heart disease. To add to the gloom the numbers are going up not down so the prediction is 150,000 new cancer cases in 2020.

Not a lot and no surprise

Well, you may be thinking, no change there then – or even I told you so. After all, I’m forever in these pieces elaborating on current cancer stories holding forth about how slow is the progress of science: one step forward, two back, more of a shuffle than a step really, and so on. Or as Martin Schwartz more eloquently puts it, describing science as the art of productive stupidity – being ignorant by choice. This follows almost inevitably from the nature of research because working on what we don’t understand puts us in the awkward position of being ignorant. As Schwartz has it, one of the beautiful things about science is that it allows us to bumble along, getting it wrong time after time, and feel perfectly fine as long as we learn something each time. That’s why I keep telling you to ignore the “great breakthough” newspaper headline dribble – that’s just the hacks trying anything to persuade their editors to give them space to promote themselves.

But wait a mo.

All that sounds consistent with the signs that things in Oz have been going backwards at a rate of knots over the last 20-odd years. But hang on. As ever, bare stats can be a bit misleading (remember what Disraeli said). Thus although around 19,000 more people die each year from cancer than 30 years ago, this is due mainly to population growth and aging – Australian life expectancy has gone up by over four years since 1990 (it’s now 82). The death rate from cancers has fallen by more than 16% and the survival rate for many common cancers has increased by 30 per cent in the past two decades. So that’s great: terrific ad for living in Oz and something of a triumph for medical science.

A sunny side in Oz?

What’s more you can put a positive twist on even the gloomy side of the picture by noting that, if indeed there’s strength in unity, Australia’s trends are much the same as everyone else’s in what we like to call the developed world. Well sort of but there’s a serious negative for Australia Fair, as you might put it, something that sticks out like a sore thumb (or an itchy mole) when you glance at the stats. Between 1980 and 2010 the incidence of skin cancer has shot up in Australia by around 60%. The most common type is non-melanoma skin cancer – usually treatable as it generally doesn’t spread around the body. The nasty version is malignant melanoma – which does metastasize, although is essentially curable if caught before some of its cells escape from the primary site. And the really bad news is that it is now the third most common cancer in Australians and in those aged 15-44 years it is the most common cancer. In 2012, over 12,000 Australians were diagnosed with melanoma and it killed over 1,600. This disease is usually set off by ultraviolet light from sunlight (or sunbeds) damaging DNA (i.e. causing mutations) and you will not have missed the allusion to the fact that people with fair skin (or blue or green eyes/red or blond hair) are most at risk.So the current Oz figures are a bit of a blow to Richie Benaud’s campaign of which I made great play in Slip-Slop-Slap Is Not Enough.

220px-Melanoma_vs_normal_mole_ABCD_rule_NCI_Visuals_Online

ABCD rule illustration: On the left side from top to bottom: melanomas showing asymmetry, a border that is uneven, ragged, or notched, coloring of different shades of brown, black, or tan and diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even color, no change in diameter).

Meanwhile in the lab?

It’s pretty sobering for me to reflect that it was only a few years before I went to Oz that the first human cancer gene (oncogene) was discovered. That was RAS, detected in human cancer cells in 1982 by Geoffrey Cooper at Harvard, Mariano Barbacid and Stuart Aaronson at the NIH, Robert Weinberg at MIT and Michael Wigler at Cold Spring Harbor Laboratory. Between then and 2003 several hundred more cancer genes were identified in a huge frenzy of molecular stamp collecting. Then came the human genome sequencing project and in its wake analysis of tumours on a scale and level of detail that is almost stupefying and would have been unimaginable before 2003. To appreciate the mountain of cancer data that has been assembled over that period, screen the literature data base for research papers that have ‘RAS’ in the title: that is, contain significant info relating to that gene. Answer: 76,000. That’s seventy-six thousand separate pieces of research that have made it through all the peer review and editorial machinery to see the light of day in print. And RAS, massive player though it is, is not the biggest. Do the same check for a gene called P53 and the number is: over 145,000!!

Confused? The plot so far …

First up we noted that the cancer burden in Oz has got a lot heavier over the last 25 years, then we reminded you that advances in science are of the snail-like variety – so you shouldn’t be surprised when things seem to go backwards. But, flipping to the other hand, we trotted out another set of figures saying things have actually got much better (life expectancy and cancer survival rates have steadily climbed). Though, switching hands again, melanoma’s gone through the roof. However, going back to the first hand, if we can still locate it, we noted the massive explosion in the facts mountain of cancer biology for which the blue touch paper was only lit about 25 years ago.

And your parliamentary candidate is …

What with all this sleight-of-hand, flip-flopping and U-turning, it occurs to me that I’m shaping up rather well as a prospective politician. I’m quite taken with the idea, especially as if I stood as an MP in my own constituency I’d be up against Andrew Lansley who, as you’ve probably forgotten, was once upon a time Secretary of State for Health. Being a virtuous and helpful soul, when Betrayed by Nature came out I sent him a copy as a gift, a freebie, – figuring that, as a career civil servant and politician who’d become responsible for the nation’s health, he might find it useful to read a basic primer on something that was killing 150,000 UK citizens every year. Thoughtful, you’d say? Indeed. Did I expect to find him on my doorstep next day gushing gratitude and thirsting for more knowledge? Maybe not, even though he only lives round the corner and we have actually met in the dim past. But at least one might have received a note – a one line email, perhaps – from his PA, who can scarcely be too busy to be polite. But no. Nothing. Zippo. So I came up with a brief sentence that summarised my take on this example of voter wooing, or indeed plain good manners, but I can’t remember it now – for the best perhaps. What is it the Bible says about getting narked? Something along the lines of “whoever says, ‘You fool!’ shall be liable to the hell of fire.”

So thank heavens we’ve side-stepped that but nevertheless, Andrew, it really would be a joy to give you a bloody nose – electorally speaking, of course – so let’s just give those credentials one more buffing. We started by lowering your expectations of science with the reminder that things proceed at a snail’s pace {you do realise that common analogy is very unfair on snails? Scientists have shown they can bowl along at a metre an hour (yippee, we do discover things!) – not much slower than your average supermarket trolley-pusher, but here’s the thing. Snail’s pace means they can get round the garden in one night. That’s the whole of their world covered in one go – without mechanical assistance!! Not so slow after all, eh?}. But the flip side is that the genomic era has already seen the development of a number of drugs that are effective against malignant melanoma. They’re not perfect but at least they take us a step further in dealing with this cancer once it has spread around the body.

And the message?

(That’s quite enough politics, Ed). OK. Let’s abandon a promising career and go back to being a scientist with a typically punchy summary. Australia’s wonderful but when it comes to cancer it’s not much different to any other rich country (not really a flip that, just a statement of fact). Folk are living longer so, of course, more of us will ‘get’ cancer but we seem to think that longevity buys us more time to smoke, booze, burn ourselves pink and eat crappy food. Medical science is doing wonders in detection and treatment: at nearly $400 million a year on cancer research, almost a quarter of all health research expenditure in Australia, it jolly well should. But if we don’t do more to help ourselves the cancer burden is going to overwhelm health resources not just ‘down under’ but all over.

Reference

Schwartz, M.A. (2008). The importance of stupidity in scientific research. J Cell Sci 2008 121:1771; doi:10.1242/jcs.033340

 

Mission Impossible?

We make great play in these pages of the wonders of the genetic revolution. So we should. The technology is simply breathtaking, and the amount of data we can gather is so incomprehensibly vast the latest generation of computers is straining at the seams to record it all and, of course, it unveils the vision of a new world. No field has felt the impact more than cancer biology which now holds the promise that, shortly after being found, tumors will be sequenced: on the basis of identified ‘driver’ mutations appropriate drug cocktails will be devised to prevent remission after the initial treatment and these can even be tested in mouse ‘avatars’ to confirm their effectiveness against the patient’s own tumor cells. Finally, even if recurrence sets in at a later date, the same procedure can be repeated and a new drug combo used to target any evolution undergone by the cancer. The era of ‘personalized medicine’ has arrived.

Every Silver Lining …

But there are a few murky clouds drifting across this sky blue portrait of triumph.

  1. The first is that, as we’ve seen in Family Tree of Breast Cancer and Molecular Mosaics, cancers are an incredible mixture – that is, the mutation signature varies depending on the region sampled in primary tumors and is different for individual metastases. This means that a ‘signature’ at best represents a dominant hand of mutations and, worse still, it’s continuously evolving.
  2. The second problem is that, although there are several hundred ‘anti-cancer’ drugs that have been approved for use by the FDA against specific types or stages of cancer, fewer than half a dozen are ‘specific’ – meaning that they hit only tumor cells and leave normal tissue alone. The ‘few’ work because they knock out the activity of mutant proteins that are made only in tumor cells. Notable examples are vemurafinib/Zelboraf (hits the mutated form of BRAF that drives a high proportion of malignant melanomas) and imatinib/Gleevec (blocks the BCR-ABL protein that is formed in most chronic myelogenous leukemias) – and these ‘targetted therapies’ have produced spectacular remissions. Other agents that have attracted much media attention include Herceptin (trastuzumab), a monoclonal antibody that sticks to a protein present in large amounts on the surface of some types of breast cancer cell. This type of agent is highly specific for the protein it targets (i.e. it doesn’t interact with anything else) but it isn’t specific for cancer cells per se. They work because cells heavily loaded with the target get a relatively big hit – a kind of tall poppy syndrome.
  3. Virtually all other chemo agents work on the same principle: in essence they affect every cell they manage to reach and any anti-cancer effect is due to tumor cells being a bit more susceptible. Which is why, of course, the efficacy of any drug combo is to a considerable extent a matter of luck and side effects are such a common problem.
  4. Unquestionably more anti-cancer drugs will be developed, those that do come on line will be more specific and therefore less unpleasant to use, so it may well be that in 20 years time we will have a drug cabinet that is sufficiently well stocked to tackle the major cancers at key stages in their evolution. Which is all well and good but, regardless of how they work and what is meant by ‘specificity’, the biggest problem of all will remain. Resistance – the capacity of tumor cells to neutralize anything that is used with the idea of neutralizing them. They do this by two main routes (1) pumping out the drug and (2) adapting to reduce drug efficacy. The obvious counter is simply to throw more of the drug at them but, in the end, side-effects impose a limit. What this means is that even when drugs have initially startling effects, as do vemurafinib and imatinib, patients eventually become refractive and tumors recur.

MAPK

Cell signalling: cells receive many signals from messengers that attach to receptor proteins spanning the outer membrane. Activated receptors turn on relays of proteins (RAS, A, B, C, D) that talk to the nucleus, switching on genes that drive proliferation. RAS proteins are a focus for many incoming signals and they also set off several relay chains that converge on the nucleus. They work at the cell membrane to which they are escorted from where they’re made by a protein called PDEdelta. A new drug, deltarasin, blocks the escort’s action so that RAS cannot find its way to work and cell growth is arrested.

A Different Line of Attack

In view of that rather gloomy assessment should we try an alternative approach? The personalized scenario involves drug combos tailored to the individual cancer at a given stage of development. But if that seems unlikely to provide a solution remotely near to the ideal, is there another way of selecting targets? Time to try ‘impersonalized medicine’ perhaps?

This notion comes from the thought that what we’re trying to do is block signals that release the brakes on cell proliferation. Many distinct signal pathways impact on the machinery that drives this process, themselves driven by different types of external signal, but it would seem obvious that somewhere along the line these must converge on one or two key regulators – master controllers if you like of cell multiplication. Indeed they do and one of these foci is a protein called RAS (there are three close relatives in the RAS family). RAS is a major junction in cell signalling: many messages from the outside world eventually converge on RAS and lots of pathways radiate from it. When a cell launches itself into the division cycle it does so as an integrated response to these signals.

RAS is mutated to a hyperactive form in about 20% of human cancers (turning on cell growth) so obviously it would be good to have a drug that can hit RAS and an enormous amount of effort has gone into coming up with one. Unfortunately a variety of clever strategies aimed directly at RAS proteins simply haven’t worked. Enter Gunther Zimmermann and his team.

Inhibiting RAS Signalling

RAS proteins do their signaling attached to the inside of the outer membrane of the cell – but they’re made in the interior and to get to their place of work they are escorted to the membrane by a protein called PDEδ (a phosphodiesterase). To upset this cosy arrangement, the Dortmund group developed small molecule, deltarasin, that sticks tightly to the escort which, in response, changes shape just enough to prevent it being able to hold hands  with RAS. The result is that the key signaller (KRAS in fact) is no longer distributed to the membrane. This prevents it working and impairs the growth of KRAS-mutant pancreatic tumour cells.

The great attraction of this approach is that it’s indirect – so the hope is that cells won’t realize that RAS is wandering aimlessly around doing nothing and therefore not simply overwhelm the drug by making more mutant RAS. It remains to be seen how many off-target effects this drug has but for the moment an exciting new idea holds the promise of hitting cancers where it hurts them most – in a key node essential for unregulated cell growth.

References

Baker, N.M. and Der, C.J. (2013). Cancer: Drug for an ‘undruggable’ protein. Nature 497, 577–578.

Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S.A., Triola, G., Wittinghofer, A., Bastiaens, P.I.H. and Waldmann, H. (2013). Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signaling. Nature 497, 638–642.

Obesity and Cancer

Science, you could say, comes in two sorts. There’s the stuff we more or less understand – and there’s the rest. We’re pretty secure with the earth being round and orbiting the sun, the heart being a pump connected to a network of tubes that keeps us alive, DNA carrying the genetic code – and a few other things. But human beings are curious souls and we tend to be fascinated by what we don’t know and can’t see – why the Dance of the Seven Veils caught on, I guess.

Scientists are, of course, the extreme example – they spend their lives pursuing the unknown (and, as Fred Hoyle gloomily remarked, they’re always wrong and yet they always go on). But in this media era they pay a public price for their doggedness because they get asked the pressing questions of the moment. Is global warning going to finish us off soon, why is British sport generally so poor and – today’s teaser – does being fat make you more likely to get cancer?

A few facts go a long way

The major cancers have become familiar because the numbers afflicted are so staggering – but the one good thing is that the epidemiology can tell us something about the disease. Thus for cancers of the bowel, endometrium, kidney, oesophagus and pancreas and also for postmenopausal breast cancer there is clear evidence that being overweight or obese makes you more susceptible. In other words, if you compare large groups with those cancers to equally large numbers without, the disease groups contain significantly more people who are fat. We should add that the above list is conservative. A number of other cancers are almost certainly more common in those who are overweight (brain, thyroid, liver, ovary, prostate and stomach tumours as well as multiple myeloma, leukaemia, non-Hodgkin lymphoma and malignant melanoma in men).

Sizing up the problem

The usual measure is Body Mass Index (BMI) – your weight (in kilograms) divided by the square of your height (in metres). A BMI of 25 to 29.9 and you’re overweight; over 30 is obese. In England in 2009 just over 61% of adults and 28% of children (aged 2-10) were overweight or obese and of these, 23% of adults and 14% of children were obese. And every year these figures get bigger.

How big is the risk?

Impossible to say exactly – for one thing we don’t know how long you need to be exposed to the risk (i.e. being overweight) for cancer to develop but in 2010 just over 5% of the total of new cancer cases in the UK was due to excess weight. That’s another conservative estimate, but it means at least 17,000 out of 309,000 cases, with bowel and breast cancers being the major sites.

What’s going on?

Showing an association is a good start but the important thing is to find out which molecules make that link. For obesity and cancer detail remains obscure but broad outlines are emerging, summarised in the sketch. In obesity fat (adipose) cells increase in both number and size (so it’s a double problem: more cells – and the fat cells themselves are fatter). As this happens other cells are recruited to adipose tissue and, from this cellular cooperative, signalling proteins are released that have the potential to drive tumours. This picture is similar to that of the microenvironment of tumours themselves, where many types of cell infiltrate the new growth. Initially this inflammatory and immune response aims to kill the tumour but if it fails the balance of signalling shifts so that it actually helps the tumour grow. In addition to signals from fat cells themselves, obesity is usually associated with increased levels of circulating growth hormones (e.g., insulin) and of lipids, both of which may also promote tumour development.

Thus many signals with cancerous potential arise in obese individuals. In principle these could initiate tumour growth or they could accelerate it in cancers that have started to develop independently of obesity. So it is complicated – but at least as new signalling strands emerge they offer new targets for drug therapy.

In obesity abnormal signals from fatty tissue can combine with others arising from perturbed metabolism to help cancers develop

Reference

World Cancer Research Fund (WCRF) Panel on Food, Nutrition, Physical Activity, and the Prevention of Cancer (WCRF, 2007).