Desperately SEEKing …

These days few can be unaware that cancers kill one in three of us. That proportion has crept up over time as life expectancy has gone up — cancers are (mainly) diseases of old age. Even so, they plagued the ancients as Egyptian scrolls dating from 1600 BC record and as their mummified bodies bear witness. Understandably, progress in getting to grips with the problem was slow. It took until the nineteenth century before two great French physicians, Laënnec and Récamier, first noted that tumours could spread from their initial site to other locations where they could grow as ‘secondary tumours’. Munich-born Karl Thiersch showed that ‘metastasis’ occurs when cells leave the primary site and spread through the body. That was in 1865 and it gradually led to the realisation that metastasis was a key problem: many tumours could be dealt with by surgery, if carried out before secondary tumours had formed, but once metastasis had taken hold … With this in mind the gifted American surgeon William Halsted applied ever more radical surgery to breast cancers, removing tissues to which these tumors often spread, with the aim of preventing secondary tumour formation.

Early warning systems

Photos of Halsted’s handiwork are too grim to show here but his logic could not be faulted for metastasis remains the cause of over 90% of cancer deaths. Mercifully, rather than removing more and more tissue targets, the emphasis today has shifted to tumour detection. How can they be picked up before they have spread?

To this end several methods have become familiar — X-rays, PET (positron emission tomography, etc) — but, useful though these are in clinical practice, they suffer from being unable to ‘see’ small tumours (less that 1 cm diameter). For early detection something completely different was needed.

The New World

The first full sequence of human DNA (the genome), completed in 2003, opened a new era and, arguably, the burgeoning science of genomics has already made a greater impact on biology than any previous advance.

Tumour detection is a brilliant example for it is now possible to pull tumour cell DNA out of the gemisch that is circulating blood. All you need is a teaspoonful (of blood) and the right bit of kit (silicon chip technology and short bits of artificial DNA as bait) to get your hands on the DNA which can then be sequenced. We described how this ‘liquid biopsy’ can be used to track responses to cancer treatment in a quick and non–invasive way in Seeing the Invisible: A Cancer Early Warning System?

If it’s brilliant why the question mark?

Two problems really: (1) Some cancers have proved difficult to pick up in liquid biopsies and (2) the method didn’t tell you where the tumour was (i.e. in which tissue).

The next step, in 2017, added epigenetics to DNA sequencing. That is, a programme called CancerLocator profiled the chemical tags (methyl groups) attached to DNA in a set of lung, liver and breast tumours. In Cancer GPS? we described this as a big step forward, not least because it detected 80% of early stage cancers.

There’s still a pesky question mark?

Rather than shrugging their shoulders and saying “that’s science for you” Joshua Cohen and colleagues at Johns Hopkins University School of Medicine in Baltimore and a host of others rolled their sleeves up and made another step forward in the shape of CancerSEEK, described in the January 18 (2018) issue of Science.

This added two new tweaks: (1) for DNA sequencing they selected a panel of 16 known ‘cancer genes’ and screened just those for specific mutations and (2) they included proteins in their analysis by measuring the circulating levels of 10 established biomarkers. Of these perhaps the most familiar is cancer antigen 125 (CA-125) which has been used as an indicator of ovarian cancer.

Sensitivity of CancerSEEK by tumour type. Error bars represent 95% confidence intervals (from Cohen et al., 2018).

The figure shows a detection rate of about 70% for eight cancer types in 1005 patients whose tumours had not spread. CancerSEEK performed best for five types (ovary, liver, stomach, pancreas and esophagus) that are difficult to detect early.

Is there still a question mark?

Of course there is! It’s biology — and cancer biology at that. The sensitivity is quite low for some of the cancers and it remains to be seen how high the false positive rate goes in larger populations than 1005 of this preliminary study.

So let’s leave the last cautious word to my colleague Paul Pharoah: “I do not think that this new test has really moved the field of early detection very far forward … It remains a promising, but yet to be proven technology.”

Reference

D. Cohen et al. (2018). Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 10.1126/science.aar3247.

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The Shocking Effect of Boiled Bugs

There’s never a dull moment in science – well, not many – and at the moment no field is fizzing more than immunotherapy. Just the other day in Outsourcing the Immune Response we talked about the astonishing finding that cells from healthy people could be used to boost the immune response – a variant on the idea of taking from patients cells that attack cancers, growing them in the lab and using genetic engineering to increase potency (generally called adoptive cell therapy).

A general prod

Just when you thought that was as smart as it could get, along comes Angus Dalgleish and chums from various centres in the UK and Spain with yet another way to give the immune system a shock. They used microorganisms (i.e. bugs) as a tweaker. The idea is that bacteria (that have been heat-killed) are injected, they interact with the host’s immune system and, by altering the proteins expressed on immune cells (macrophages, natural killer cells and T cells) can boost the immune response. That in turn can act to kill tumour cells. It’s a general ‘immunomodulatory’ effect. Dalgleish describes it as “rather like depth-charging the immune system which has been sent to sleep”. Well, giving it a prod at least.

bugs-pic

Inactivating bugs (bacteria) and waking up the immune system.

And a promising effect

The Anglo-Spanish effort used IMM-101 (a heat-killed suspension of a bacterium called Mycobacterium obuense) injected under the skin, which has no significant side-effects. The trial was carried out in patients with advanced pancreatic cancer, a disease with dismal prognosis, and IMM-101 immunotherapy was combined with the standard chemotherapy drug (gemcitabine). IMM-101increased survival from a median of 4.4 months to 7 months with some patients living for more than a year and one for nearly three years.

Although the trial numbers are small as yet, this is a very exciting advance because it looks as though immunotherapy may be able to control one of the most serious of cancers in which its incidence nearly matches its mortality.

References

Dalgleish, A. et al. (2016). Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. British Journal of Cancer doi: 10.1038/bjc.2016.271.

 

New Era … Or Déjà vu?

 

Readers who follow events in the US of A – beyond the bizarre unfolding of the selection of the Republican Party’s nominee for President of the United States – may have noticed that the presidential incumbent put forward another of his bright ideas in the 2016 State of the Union Address. The plan launched by President Obama is to eliminate cancer and to this end $1 billion is to go into a national initiative with a strong focus on earlier detection, immunotherapy and drug combinations. It’s called a Moonshot’, presumably as a nod to President Kennedy’s 1961 statement that America should land a man on the moon (and bring him back!).011316_SOTU_THUMB_LARGE

A key aim of Moonshot is to improve all-round collaboration and to ‘bring about a decade’s worth of advances in five years.’ Part of this involvesbreaking down silos’ – which apparently is business-speak (and therefore a new one on me) for dealing with the problem of folk not wanting to share things with others in the same line of work. So someone’s spotted that science and medicine are not immune to this frailty.silo_mentality

On the home front …

In fact the President could be said to be slightly off the pace as, in October 2015, Cancer Research UK launched ‘Grand Challenges’ – a more modest (£100M) drive to tackle the most important questions in cancer. They’ve pinpointed seven problems and, helpfully, six of these will not be new to dedicated readers of these pages. They are:

  1. To develop vaccines (i.e. immunotherapy) to prevent non-viral cancers;
  2. To eradicate the 200,000 cancers caused each year by the Epstein Barr Virus;
  3. To understand the mutation patterns caused by different cancer-causing events;
  4. To improve early detection;
  5. To map the complexity of tumours at the molecular and cellular level;
  6. To find a way of targetting the cancer super-controller MYC;
  7. To work out how to target anti-cancer drugs to specific cells in the body.

{No/. 2 is the odd one out so it clearly hasn’t been too high a priority for me but we did talk about Epstein Barr Virus in Betrayed by Nature – phew!}.

But wait a minute

Readers of a certain age may be thinking this all sounds a bit familiar and, of course, they’re right. It was in 1971 that President Richard Nixon launched the ‘war on cancer’, the aim of which was to, er, to eliminate cancers. Given that 45 years on in the USA there’ll be more than 1.6 million new cases of cancer and 600,000 cancer deaths this year, it’s tempting to conclude that all we’ve learned is that things are a lot more complicated than we ever imagined.

Well, you can say that again. Of the several hundred genes that we now know can play a role in cancers, two are massively important MYC (‘mick’) and P53. Screen the scientific literature for research publications with one of those names in the title and you get, wait for it, over 50,000 for ‘MYC’ and for P53 over 168,000. It’s impossible to grasp how many hours of global sweat and toil went into churning out that amount of work – and that’s studies of just two bits of the jigsaw!

So 45 years of digging have yielded astonishing detail of the cellular and molecular biology – and that basis will prove essential to any rational approach to therapy. It’s a slow business this learning to walk before you run! But we can be rather more up-beat. Alongside all the science there have come considerable improvements in treatments. Thirty years ago one in four of those diagnosed with a cancer survived for more than 10 years. Now it’s almost one in two. But it’s a hugely variable picture: for breast cancer the 10 year overall survival rate is nearly 80% and for testicular cancer it’s over 98%. However, for lung cancer and cancer rates remain below 5% 1%, respectively. For these and other cancers there has been very little progress.

So 45 years of digging away have yielded astonishing detail of the cellular and molecular biology – and that basis will prove essential to any rational approach to therapy. It’s a slow business this learning to walk before you run! But we can be rather more up-beat. Alongside all the science there have come considerable improvements in treatments. Thirty years ago one in four of those diagnosed with a cancer survived for more than 10 years. Now it’s almost one in two. But it’s a hugely variable picture: for breast cancer the 10 year overall survival rate is nearly 80% and for testicular cancer it’s over 98%. However, for lung cancer and pancreatic cancer rates remain below 5% and 1%, respectively. For these and other cancers there has been very little progress.

All systems go?

Well, maybe. Moonshot is aimed at better and earlier diagnosis, more precise surgery and radiotherapy, and more drugs that can be better targeted. Oh, and bearing in mind that one in three cancers could be prevented, keeping plugging away at lifestyle factors.

How will it fare? Well, now we’re in the genomic era we can be sure that the facts mountain resulting from 45 years of collective toil will be as a molehill to the Everest of data now being mined and analysed. From that will emerge, we can assume with some confidence, a gradual refinement of the factors that are critical in determining the most effective treatment for an individual cancer.

Just recently we described in The Shape of Things to Come the astonishingly detailed picture that can be drawn of an individual tumour when it’s subjected to the full technological barrage now available. As we learn more about the critical factors, immunotherapy regimens will become more precise and the current response rate of about 10% of patients will rise.

Progress will still be slow, as we noted in The Shape of Things to Come – don’t expect miracles but, with lots of money, things will get better.

Dennis’s Pet Menace

As it happened, I’d already agreed to appear on Jeremy Sallis’ Lunchtime Live Show on BBC Radio Cambridgeshire – the plan being just to chat about cancery topics that might be of interest to listeners. Which would have been fine – if only The World Health Organization had left us in peace. But of course they chose last Tuesday to publish their lengthy cogitations on the subject of whether meat is bad for us – i.e. causes cancer.

Cue Press extremism: prime example The Times, quite predictably – they really aren’t great on biomedical science – who chucked kerosene on the barbie with the headline ‘Processed meats blamed for thousands of cancer deaths a year’.

But – to precise facts – and strictly it’s The International Agency for Research on Cancer, the cancer agency of the World Health Organization (WHO), that has ‘evaluated the carcinogenicity of the consumption of red meat and processed meat.’

But hang on … haven’t we been here before?

Indeed we have. As long ago as January 2012 in these pages we commented on the evidence that processed meat can cause pancreatic cancer and in May of the same year we reviewed the cogitations of the Harvard School of Public Health’s 28 year study of 120,000 people that concluded eating red meat contributes to cardiovascular disease, cancer and diabetes. To be fair, that history partially reflects why the WHO Working Group of 22 experts from 10 countries have taken so long to go public: they reviewed no fewer than 800 epidemiological studies! However, as the most frequent target for study was colorectal (bowel) cancer, that was the focus of their report released on 26th October 2015.

So what are we talking about?

Red meat, which means any unprocessed mammalian muscle meat, e.g., beef, veal, pork, lamb, mutton, horse or goat meat, that we usually cook before eating.

Processed meat: any meat not eaten fresh that has been salted, cured, smoked or whatever and commonly treated with chemicals to enhance flavour and colour and to prevent the growth of bacteria.

What did they say?

Processed meat is now classified as carcinogenic to humans – that is it goes into the top group (Group 1) of agents that cause cancer.

Red meat is probably carcinogenic to humans (Group 2A). Group 2B is for things that are possibly carcinogenic to humans.

Why?

Because 12 of the 18 studies they reviewed showed a link between consumption of processed meat and bowel cancer and because it’s known that agents commonly added to processed meat (nitrates and nitrites) can, when we eat them, turn into chemicals that can directly damage DNA, i.e. cause mutations and hence promote cancers.

For red meat 7 out of 15 studies showed positive associations of high versus low consumption with bowel cancer and there is strong mechanistic evidence for a carcinogenic effect i.e. when meat is cooked genotoxic (i.e. DNA-damaging) chemicals can be generated. They put red meat in the probably group because several of the studies that the Working Group couldn’t fault – and therefore couldn’t leave out – showed no association.

Stop woffling

My laptop likes to turn ‘woffling’ into ‘wolfing’. Maybe it’s trying to tell me something.

But is The WHO trying to tell us something specific about wolfing? To be fair, they have a go by estimating that every 50 gram portion of processed meat (say a couple of slices of bacon) eaten daily increases the risk of bowel cancer by about 18%. For red meat the data ‘suggest’ that the risk of bowel cancer could increase by 17% for every 100 gram portion eaten daily.

And what might that mean?

In the UK about 6 people in 100 get bowel cancer: if you take The WHO maximum estimate and have everyone eat 50 grams of processed meat every day of their lives such that 18% more of them would get bowel cancer, the upshot would be 7 people in 100 rather than 6. So it’s a small rise in a relatively small risk.

As the report points out, the Global Burden of Disease Project reckons diets high in processed meat cause about 34,000 cancer deaths per year worldwide and, if the reported associations hold up, the figure for red meat would be 50,000. Compare those figures with smoking that increases the risk of lung cancer by 20-fold and The WHO’s estimate of up to 6 million cancer deaths per year globally caused by tobacco use and 600,000 per year by alcohol consumption.

All of which suggests that it isn’t very helpful to lump meat eating, tobacco and asbestos in the same cancer-causing category and that The WHO could do worse than come up with a new classification system.

And the message?

Unchanged. Remember mankind evolved into the most successful species on the planet as a meat eater. As the advert used to say: It looks good, it tastes good and by golly it does you good – not least as a source of protein, vitamins and other nutrients. Do some exercise and eat a balanced diet – just in case you’ve forgotten, that means limit the amount of red meat (The WHO suggests no more than 30 grams a day for men, 25 g for women) so try fish, poultry, etc. Stick with the ‘good carbs’ (vegetables, fruits, whole grains, etc.), cut out the ‘bad’ (sugar – see Biting the Bitter Bullet), eat fishy fats not saturated fats and, to end on a technical note, don’t pig out.

_65259128_6136791400_49fc5aaece_b

‘The Divine Swine’ Castelnuovo Rangone, Italy

Meanwhile back on the Beeb

When the meat story broke I was a bit concerned that we might end up spending the whole of Lunchtime Live on how many bangers are lethal – especially as we were taking calls from listeners. Just in case things became a bit myopic I had Rasher up my sleeve. Rasher, you may recall, was Dennis the Menace‘s pet pig (in the The Beano‘s comic strip) who had a brother (Hamlet), a sister (Virginia Ham) and various other porky rellos. To bring it up to date we’d have introduced Sam Salami and Frank Furter and, of course, Rasher’s grandfather who was the model for the bronze statue named ‘The Divine Swine’ to be found in the little town of Castelnuovo Rangone in Pig Valley, Italy, the home of Parma ham.

But I shouldn’t have worried. All was well in the hands of Jeremy Sallis who, being a brilliant host, ensured that we mainly chatted about meatier matters than what to have for breakfast.

References

Press release: IARC Monographs evaluate consumption of red meat and processed meat.

Q&A on the carcinogenicity of the consumption of red meat and processed meat.

Carcinogenicity of consumption of red and processed meat. www.thelancet.com/oncology Published online October 26, 2015

Lethal ZIP codes

In Keeping Cancer Catatonic we retailed how, over 125 years ago, the London physician Stephen Paget came up with his ‘seed and soil’ idea to explain why it was that when cancers spread to distant sites around the body by getting into the circulation they didn’t simply stick to the first tissue they came across. Paget had spotted that cancers tend to have preferred sites for spreading: tumours of the eye tend to travel to the liver, rather than the much handier brain, and breast cancers, Paget’s speciality, commonly spread to the liver but also to the lungs, kidneys, spleen and bone. So his idea was that certain distant secondary sites are somehow made more receptive to tumor growth, just as soil can be prepared for seeds to sprout.

So the key question became ‘how?’ and it’s hung in the cancer air for well over a century during which we’ve made very little progress towards an answer – and it is crucial because the business of tumour cells spreading (metastasizing) causes most cancer deaths (over 90%).

But, at long last, things have started to move, largely due to the efforts of David Lyden and his colleagues at Weill Cornell Medical College. Their first astonishing contribution was to show that cells in primary tumours release messengers into the circulation and these, in effect, tag what will become landing points for wandering tumour cells – i.e., the target sites are determined before any tumour cells actually set foot outside the confines of the primary tumour.

After that seismic revelation the story advanced a step further (in Scattering the Bad Seed) with some molecular detail of how the sites are marked – an effect Lyden has christened ‘Bookmarking cancer’ – and how when tumour cells do settle in their new niche they may be kept dormant for many years before starting to expand.

Carrying the flag

The next chapter in the story, as retailed in Holiday Reading (4) – Can We Make Resistance Futile?, revealed that the message is carried by small sacs – like little cells – called exosomes that are released from tumour cells. These float around the circulation until they find their target site, whereupon they plant the flag by setting off a chain reaction that produces a sticky protein – fibronectin – a kind of glue for immune cells and tumour cells.

That is all truly amazing stuff but, as we noted in Holiday Reading (4) – Can We Make Resistance Futile?, a recurring theme in science is that one answer merely poses the next question – in this case ‘what’s the messenger?’

As in all the best thrillers, the authors have kept us in suspense to the last, helped presumably by their not knowing the answer. But in this week’s Nature (Oct. 28, 2015) comes the denoument to this whodunit.

Mister postman look and see …

Many moons ago an outfit called the Marvelettes had a No. 1 hit with Please Mr. Postman and somewhat later the Fab Four did a re-hash that met with equal success. Perhaps we should have asked them how nature would go about directing little packages around the body. John, Ringo and the lads would, with their earthy, Liverpudlian logic, have pointed out the triviality of the problem of exosome addressing. ‘It’s not like you’re sending stuff all over the world, is it? You’ve only got a few targets – the major organs of the body. So a dead simple code will do. You know your messengers are proteins – ’coz they do everything – OK? So, pick a protein that comes in two bits with a few variants of each: mix and match and there’s yer postcodes. Now … what was that ditty about yellow subsurface vessels …’

And so it came to pass …

And the messenger is …

A family of proteins called integrins whose job is to span the membranes of cells, thereby promoting cell-cell interactions. They are indeed made of two different chains stuck together (called α (alpha) and β (beta)) and the upshot is that our cells can make about 24 unique integrins – more than enough to form a coded address system to direct tumour cells around the body. Well done lads!

What Ayuko Hoshino, David Lyden and their many collaborators did was to tag exosomes released from various types of cancer cell with a fluorescent dye and inject them into mice. The fluorescent label enabled them to track the exosomes and it turned out that, for a variety of cancer cells (breast, pancreatic, colorectal, lung, melanoma and pediatric) the exosomes travelled to the organs associated with metastasis (e.g., breast cancer exosomes stuck in the lungs, pancreatic cancer exosomes in the liver, etc). In other words exosome spread mimicked the pattern of the tumour from which they were derived. Once they had landed the exosomes set about reprogramming the organ sites to make a fertile microenvironment capable of supporting tumor cell growth in a new colony.

When they looked at the exosome proteins they found a particular member of the integrin family flagged each organ-specific site. Thus α6β4 promotes lung metastasis, αvβ5 homes in on the liver, αvβ3 on the brain, etc.

MapFinding a home

To spread around the body (metastasise) primary tumours first release small sacs (exosomes) carrying protein tags (integrins). Moving through the circulatory system the integrin tags home in to specific addresses found on different organs. The effect of exosomes sticking to target sites is to prepare the ground for cells released by the tumour to adhere and colonise.

Down the tube

You could think of primary tumours as being a bit like us when we move to a new city and try to find a des. res. in a place you don’t know. We could just ramble round the subway system until something catches our eye but that might take for ever. Much more efficient is to ask someone with local knowledge where would be good spots to target. For disseminating tumours their exosomes are the scouts who do the foot-slogging: the protein signatures on the surface of these small, tumour-secreted packages home in on postcodes that define a desirable locale for metastatic spread.

Shooting the messenger

An obvious question is ‘If exosomes are critical in defining metastatic sites, can you block their action – and what happens when you do?’ In preliminary experiments Hoshino & Co showed that either knockdown of specific integrins or blocking the capacity of these proteins to stick to their targets (with a specific antibody or short synthetic peptides) significantly reduced exosome adhesion, thereby blocking pre-metastatic niche formation and liver metastasis.

A new beginning?

We described these fabulous results as the denouement but, of course, it isn’t. As Mr. Churchill remarked in a somewhat different context: ‘Now this is not the end.’ It is rather a step to answering an old question but it’s incredibly exciting. If screening for exosomes leads to the detection of cancer not just years but perhaps decades earlier than can be achieved by present methods and if blocking their action can keep metastasis at bay, then the field of cancer will be utterly transformed.

References

Hoshino, A. et al. (2015). Tumour exosome integrins determine organotropic metastasis. Nature doi:10.1038/nature15756.

Ruoslahti, E. (1996). RGD and Other Recognition Sequences for Integrins. Annual Review of Cell and Developmental Biology 12, 697-715.

A Small Helping For Australia

There’s an awful lot of very good things in Australia. Australians for a start. They’re just so kind, open, welcoming and accommodating it makes touring round this vast land a joy. Not merely do they cheerfully find a way to fix anything you want but they’re so polite that no one’s drawn attention to my resemblance to a scientific version of those reconstructed geriatric pop groups (viz the Rolling Stones or whatever) staggering round the place on their Zimmer frames. And they say wonderful things about my talks – that’s how charming they are!!

Greater bilgy

Greater bilby

Of course, you could say of Australia what someone once said of America and Britain: two nations divided by a common language. In the case of Oz you could also add ‘and by a ferociously competitive obsession with sport.’ So it’s wonderfully not home. Even Easter’s different in that here you get chocolate Easter bilbies rather than rabbits. Bilbies, by the way, are a sort of marsupial desert rat related to bandicoots. The lesser version died out in the 1950s so only the greater bilby is left (up to 20 inches long + tail half as long again) and you have to go to the arid deserts to find those. Not the choccy versions obviously: they don’t do too well in the deserts but they’re all over Melbourne:

Easter bilby

Easter bilby

shops full of ’em – and a lot bigger than the real thing. So, together with the egg avalanche, there’s no limit to the number of calories you can consume in celebrating the resurrection of Christ. Coupled with the glorious fact that there’s scarcely any mention of wretched soccer, all these novelties mean you’re never going to be lulled into thinking you’re still in dear old Blighty (or back in the old country as they delightfully put it here).

Hors D’Oeuvres

Even so there are some marked similarities to make you feel at home. One of the least striking is that most people are overweight. That is, I scarcely notice it, coming from what I regard as the global fat capital, i.e. Cambridge. The stats say that that’s not true, of course. The USA does these things better than the UK. Of course it does. But there’s not much in it. More than two-thirds of American adults are overweight and one person in three is obese. For the UK the prediction is that one in three will be obese by 2020. Currently in Australia 63% of the adult population is overweight, a figure that includes 28% who are obese.

The essential point is that there’s stuff all difference between those countries and the really critical thing is that the rates go on soaring. In the U.S. between 1980 and 2000 obesity rates doubled among adults and since 1980 the number of overweight adolescents has tripled. By 2025 one Australian child in three will be in the overweight/obese category.

Main course

The meat in this piece is provided by a report written by a bunch of Australian heavyweights – all Profs from Sydney or wherever. It has the droll title ‘No Time To Weight’ – do I need to explain that or shall I merely apologise for the syntax? ‘Oh c’mon!’ I hear our Aussie readers protest. ‘We’re going to hell in a handcart and you’re wittering about grammar. Typical b***** academic.’ Quite so. Priorities and all that. So the boffins’ idea is to wake everyone up to obesity and get policy-makers and parliamentarians to do something effective.No Time to Weight report

Why is this so important? Probably unnecessary to explain but obesity causes a variety of disorders (diabetes, heart disease, age-related degenerative disease, sleep apnea, gallstones, etc.) but in particular it’s linked to a range of cancers. Avid followers of this BbN blog will recall obesity cropping up umpteen times already in our cancer-themed story (Rasher Than I Thought?/Biting the bitter bullet/Wake up at the back/Twenty winks/Obesity and Cancer/Isn’t Science Wonderful? Obesity Talks to Cancer) and that’s because it significantly promotes cancers of the bowel, kidney, liver, esophagus, pancreas, endometrium, gallbladder, ovaries and breast. The estimate is that if we all had a body mass index (BMI) of less than 25 (the overweight threshold) there would be 12,000 fewer UK cancers per year. Mostly the evidence is of the smoking gun variety: overweight/obese people get these cancers a lot more often than lesser folk but in Obesity Talks to Cancer we looked at recent evidence of a molecular link between obesity and breast cancer.

Entrée (à la French cuisine not North American as in Main course)

Or, as you might say, a side dish of genetics. The obvious question about obesity is ‘What causes it?’ The answer is both complicated and simple. The complexity comes from the gradual accumulation of evidence that there is a substantial genetic (i.e. inherited) component. Many people will have heard of the hormone leptin, a critical regulator of energy balance and therefore of body weight. Mutations in the leptin gene that reduce the level of the hormone cause a constant desire to eat with the predictable consequence. But only a very small number of families have been found who carry leptin mutations and, although other mutations can drive carriers to overeating, they are even rarer.

However, aside from mutations, everyone’s DNA is subtly different (see Policing DNA) – about 1 in every 1000 of the units (bases) that make up our genetic code differs between individuals. All told the guess is that in  90% of the population this type of genetic variation can contribute to their being overweight/obese.

Things are made more complicated by the fact that diet can cause changes in the DNA of pregnant mothers (what’s called an epigenetic effect). In short, if a pregnant woman is obese, diabetic, or consumes too many calories, the obesity trait is passed to her offspring. This DNA ‘imprinting’ activates hormone signaling to increase hunger and inhibit satiety, thereby passing the problem on to the child.Preg Ob

So the genetics is quite complex. But what is simple is the fact that since 1985 the proportion of obese Australians has gone up by over 10-fold. That’s not due to genes misbehaving. As David Katz, the director of Yale University’s Prevention Research Center puts it: ‘What has changed while obesity has gone from rare to pandemic is not within, but all around us. We are drowning in calories engineered to be irresistible.’

Desserts

We might hope that everyone gets theirs but for obesity that’s not the way it works. The boffos’ report estimates that in 2008 obesity and all its works cost Australia a staggering $58.2 billion. Which means, of course, that every man, woman and child is paying a small fortune as the epidemic continues on its unchecked way. The report talks formulaically of promoting ‘Australia-wide action to harmonise and complement efforts in prevention’ and of supporting treatment. It’s also keen that Australia should follow the American Medical Association’s 2013 decision to class obesity as a disease, the idea being that this will help ‘reduce the stigma associated with obesity i.e. that it is not purely a lifestyle choice as a result of eating habits or levels of physical activity.’ Unfortunately this very p.c. stance ignores that fact that obesity is very largely the result of eating habits coupled to levels of physical activity. The best way to lose weight is to eat less, eat more wisely and exercise more.

In 2008 Australian government sources forked out $932.7 million over 9 years for preventative health initiatives, including obesity. This latest report represents another effort in this drive. Everyone should read it but, clear and well written though it is, it looks like a government report, runs to 34 pages and almost no one will give it the time of day.

The problem is that in Australia, as in the UK and the USA, all the well-intentioned propaganda simply isn’t working. As with tobacco, car seat belts and alcohol driving limits, the only solution is legislation, vastly unpopular though that always is – until most folk see sense. Start with the two most obvious targets: ban the sale of foods with excessive sugar levels (especially soft drinks) and make everyone have a BMI measurement at regular intervals, say biannually. Then fine anyone over 25 in successive tests who isn’t receiving some sort of medical treatment.

Amuse bouche

I know: I’ll never get in on that manifesto. But two cheers for ‘No Time To Weight’ and I trust the luminaries who complied it appreciate my puny helping hand from Cambridge. In the meantime, not anticipating any progress on a national front, I’m going to start my own campaign – it’s going to be a bit labour-intensive, one target at a time, but here goes!

The other evening I had dinner in a splendid Italian restaurant (The Yak in Melbourne: very good!). And delightful it would have been had I not shared with two local girls at the next table. One was your archetypal tall, slender, blonde, 25-ish Aussie female – the sort you almost feel could do with a square meal. Her companion of similar age was one of the dirigible models. (You’ll understand I wasn’t looking at them at all: I was with my life’s companion so no chance of that – but I do have very good peripheral vision. Comes from playing a lot of rugby). Each had one of the splendid pasta dishes on offer – but, bizarrely, they also ordered a very large bowl of chips. No prizes for guessing who ate all the fries. Miss Slim didn’t have one – not a single one! (OK, by now I was counting). Her outsize friend had the lot. How could she do that with a shining example of gastronomic sanity sitting opposite?

So c’mon Miss Aussie Airship: you know who you are. Let’s have no more of it. Obesity is not a personal ‘issue.’ Regardless of your calorie intake in one meal, your disgraceful behavior ruined a delightful dining experience for me, and quite possibly several other folk within eyeshot, upset the charming waitress and insulted The Yak’s excellent chef. Just think in future: there’s a place in life for chips – but it’s not with everything.

Reference

“Obesity: A National Epidemic and its Impact on Australia”

Scattering the Bad Seed

Cancers are very peculiar diseases. One of their fairly well-known oddities is that, by and large, it’s not the initial tumour that does the damage – rather that the vast majority of fatalities arise from its offshoots, secondary growths formed by cells escaping from the primary and spreading around the body, a diaspora called metastasis. That ‘vast majority’ is actually over 90% – so you might suppose most research effort would be focussed on how cells disseminate and what can be done to stop them in their tracks, whilst leaving the surgeons to deal with the primaries. But like many other things in life, logic plays a limited part in research strategy and to a great extent the boffins do what they fancy – or, to make it sound a bit more rigorous, what they feel is possible given the available tools. Which is perfectly reasonable: launching a project to build a radio would have been a bit perverse before Michael Faraday discovered electricity. In short, scientific research is all about practicalities – it’s what that great science communicator (and Nobel Prize winner) Peter Medawar called The Art of the Soluble.

Metastasis on the move

We recently recounted the emergence of the notion that cancers could spread around the body and how, by the end of the 19th century, this had led to the idea of ‘seed and soil’ – that cells cast off from primary tumours could drift around the circulation until they found somewhere congenial to drop anchor and set up a new home. That was in Keeping Cancer Catatonic and it was prompted by the fact that for rather more than 100 years metastasis seemed so difficult to get at, so impossible to model, there was virtually no progress and it is only now in the last few years that this critical cancer niche is once again on the move. The really exciting, and surprising, finding has been that, in mouse models, primary tumours dispatch chemical messengers into the blood stream long before any cells set sail. These protein news-bearers essentially tag a landing site within the circulatory system for the tumour cells to follow. And which sites are tagged depends on the type of tumour – consistent with the fact that human cancers show different preferences in metastatic targets.

A further twist is that even if tumour cells manage to follow this complicated guidance system and seed a new site, it’s not a disaster because their growth is suppressed by proteins released from nearby blood vessels. This presumably reflects the fact that tissues have systems to maintain the normal balance – to ensure that unusual things don’t happen – which means that everything is fine until that control is overwhelmed. When that happens other signals convert the dormant tumour into an expanding metastasis.

These very recent discoveries show that, at long last, our ignorance of how tumours spread is beginning to be chipped away and, because metastasis is the critical issue in cancer, this is a timely moment to do one of our crystal clear, simple summaries of what we know – which is relatively easy and will take much less time than if we reviewed our ignorance.

BOOKMARKING copy

Bookmarking cancer: Primary tumours mark sites around the body to which they will spread (metastasize) by sending out chemical signals that create sticky ‘landing sites’ (red protein A) on target cells. Cells released from the bone marrow carry proteins B and C. B attaches to A and tumour cells ‘land’ on C. Cells may remain quiescent in a new site for years or decades, their growth suppressed by signals (e.g., TSP-1) released from nearby blood vessels. Only when appropriate activating signals dominate (e.g., TGF beta) is secondary tumour growth switched on (see Keeping Cancer Catatonic for more details).

So what do we know?

Tumours arise from the accumulation of (essentially) random mutations and these drive the expansion of a family of cells to the point where they make their presence felt. From that, if the bearer is unlucky, emerges a sub-set of cells with the wanderlust. Cells in which the mutational hand they have acquired confer the ability to escape from the family bosom, chew through surrounding tissue, burrow into nearby blood vessels and thus voyage to distant places around the body. Some of these adventurous fellows may find landing sites where they can stick and, in effect, reverse their escape routine by squeezing through the vessel wall and chomping their way to a new niche in which to set up home. This process is sometimes called ‘colonization’ and it’s a pretty vivid description, evoking images of brave chaps taking on the elements to find a new world in which to prosper. The upshot is a malignant tumour.

I’m sorry for pulling a sciency trick back there by inserting ‘essentially’ – in brackets to persuade you to skim over it as if it was a mild hallucination. We’ll come back to the rivetting explanation of why I’d feel uncomfortable about just saying ‘random mutations’ another day but for the moment just stick with the idea that changes in DNA make cancers.

Tumour cells are not very bright

This sequence is so convoluted that it sounds like the product of some devilish mastermind but in fact we know that the metastatic cell is incapable of thought because otherwise it would have stayed at home. Metastasis is a process so inefficient that it’s almost always fatal for the cell that tries it. Tumour cells that get into the circulation may be damaged in the rush-hour scrum that is cellular life in the bloodstream and be gobbled up by scavenger cells. Even if they do finally squeeze through a space in the wall – feeling they’ve made it – they may have suffered so much stress they’re just not up to producing a family in a new environment that mayn’t be entirely welcoming. So even after reaching a new home they may not survive any longer or just manage to form a small cluster of cells that hang on as a ‘dormant’ tumour – an indolent little outpost that represents no threat to the carrier, even though it may persist for decades. So, despite metastasis being the most life-threatening facet of cancer, the odds are strongly weighted against escaping tumour cells: even after they’ve made it into the circulation, only about one in every ten thousand makes it to a compatible site where it forms an embryonic colony.

How does it kick off?

Given that tumours are products of evolution – albeit on the hugely accelerated time-scale of an individual lifetime rather than the geological frame within which new species emerge – you might suppose that metastases are merely a potent end-product. A tumour cell continues to pick up mutations until eventually it has the required toolkit to burrow and squeeze, float and drift, touch down  on sticky patches, squeeze and burrow again and eventually thrive in a new home. In the best traditions of cancer, however, it turns out not to be like that – at least, as far as is known, no set of mutations defines cells as having acquired the tools of the spreading trade. In short, there’s no ‘genetic signature’ that uniquely marks a metastatic cell. Nevertheless, they are different: only a fraction of primary tumour cells acquire the ability to spread – so if it isn’t simply by picking up an escape kit of changes in DNA, how do they do it?

Making an escape kit

One of the things that does mark metastatic cells is a change in the genes expressed compared to their relatives in the rest of the tumour. That is they alter the pattern of proteins that they make. This switch reorganises the cell’s shape and helps it to move and, most notably, includes enzymes released into the environment that cut a path for the cell to invade its local surroundings en route to the circulation.  As you might guess, this switch in protein production appears to be reversed once a cell has found a new niche. But if this transition into an invasive (i.e. malignant) cell isn’t driven by specific mutations, how does it come about?

The answer seems to lie in a subtle fine-tuning of cell behaviour, rather than dramatic changes caused by mutations in DNA. In other words, cells emerge from the morass of mutations within a tumour with critical signal systems that are just that little bit more active than those of their companions. It’s less a tall poppy syndrome than the odd blade of grass that’s missed the mower and can see a wider world. If this still seems a bit far-fetched, recall that every cell is unique: however identical two cells may be, there will be tiny differences in the signals that control their level of response.  The minuscule edge that can give one cell over another is enough. Given time, it will reproduce to make a clone with the gymnastic ability and stamina required to embark on the fraught experience of founding a metastatic colony.

Spreading variety

One of the fascinating things about cancer is that there seems to be no absolute rules. For every generalization there’s a renegade – a piece of molecular or cellular jiggery-pokery that does it in a different way, often in a breath-taking example of Nature’s flexibility. So it is with metastasis in that, as we noted, different cancers show widely variable behaviour.  Some major types have usually spread by the time they are detected (lung, pancreatic) whereas generally breast and prostate tumours have not. Some forms of brain tumour usually invade locally and are rarely found at distant sites whilst others often metastasize. Sometimes secondary growths are found when the primary source can’t de detected at all – so they’re ‘cancers of unknown primary’ and they’re not uncommon, coming in the top 10% of diagnoses.

Equally bemusing is the range of favoured targets for dissemination. Prostate cancer cells commonly home in on bone whereas bone and muscle tumours often spread to the lungs. Others, however, are much more promiscuous and go for multiple sites (e.g., triple-negative breast cancer, skin melanoma and tumours originating in the lung and kidney). We have little idea what’s behind this variability though it may be a combination of different circulation patterns, capacity to slip through vessel walls and how well-equipped the cell is to survive in new terrain.

Making friends with the neighbours

In Cooperative Cancer Groupies we talked about one of the most recent evolutions in cancer thinking – the notion that tumours are not just made up of clumps of abnormal cells but that their locale becomes flooded with a variety of normal cells as the host mounts first an inflammatory response and then attempts to kill off the intruder through its immune system. When this defence fails and the tumour begins to develop it has succeeded in corrupting the groupies in the microenvironment so that now they send out signals that actively promote tumour growth. This type of local support is similarly critical in determining whether metastases take root, so to speak. Moreover, variation in the precise signals from normal cells between different tissues contributes to target preference for malignant cells.

Not like you see on t.v.

In the currently popular Danish political drama television series called Borgen there’s a scene in which a tabloid newspaper editor is offered a piece by a reputable journalist about the European Union that he rejects. “Don’t try to give me a story about the EU: it’s not sexy and it’s too complicated for our readers to understand.” We will have no truck with such patronising here, despite the fact that nobody ever accused metastasis of being sexy. Moreover, as no one ‘understands’ it, we take the view that we’re all in this together and, because it’s infinitely more important and fascinating than political stories, we have belaboured you with the foregoing! Just to make sure that the little we do know is clear, let us summarise in nine (more or less) one-liners:

  1. Tumor cells signal to potential secondary sites.
  2. They escape, burrow, circulate, lodge at landing sites and colonize.
  3. They change the pattern of proteins they make to permit escape.
  4. They change the pattern again when they colonize.
  5. No genetic signature (set of mutations) is known that indicates capacity to metastasize.
  6. The process is very inefficient – i.e. most tumor cells never form a colony.
  7. Despite the low success rate, metastasis is responsible for >90% of cancer deaths.
  8. Once colonization starts at secondary site, tumor cells recruit help from adjacent normal cells (as they do in primary tumors).
  9. Normal cells can also colonize – that is, non-tumour cells injected into the bloodstream of mice have been shown to form colonies in the lungs. 

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This beautiful picture taken by Bettina Weigelin and Peter Friedl, UMC St Radboud Nijmegen, shows the remarkable plasticity of cells. The tumour cells (green) are invading normal mouse skin (orange) that also contains nerve fibers (blue) and collagen (grey). Cells may invade singly or as clusters. Their flexibility in wiggling through skin is similar to what happens when they cross the walls of blood vessels. http://www.cell.com/Cell_Picture_Show

Perhaps the most surprising item is the one we slipped in at Number 9 – that metastasis, or at least the capacity to colonize secondary sites, is not an exclusively property of some tumour cells but that normal cells can do it too. For sure we assume tumour cells are better at it – not least because they can send out advance signals giving them a better chance of a happy landing. And, of course, once a colony has been founded, tumour cells already carry mutated genes that can act as ‘drivers’ for further expansion of the secondary growth. Even so, the fact that normal cells can pass from the blood to a niche in lung tissue shows that colony foundation is not a unique property of tumour cells. Lung colonization by normal cells may be down to mechanics. Your lungs, which of course fit inside your chest, resemble a sponge – a mass of fine tubes linked to 300 million air sacs (called alveoli): spread them out and they’d cover a tennis court. The alveoli are surrounded by the most intricate network of blood vessels (called capillaries) and it is here that oxygen is transferred to blood. The fine capillaries may simply be a very effective trap – cells may become stuck without the requirement for any specific markers.

And the outlook?

We have therefore a dim picture of what is involved in metastasis but the presumption is that it may rapidly brighten. It’s not hard to see why metastasis is the culprit in the overwhelming majority of cancer deaths. By spreading to new sites cancers increase enormously the difficulty of detecting them, they become almost impossible to treat by surgery and the only strategy remaining is to use drugs (chemotherapy). Currently there are hardly any treatment options available for tumours that have metastasized and even when drugs do work their effects are short lived and tumours recur. The unveiling of every new facet of the amazing puzzle that is metastasis refines our thinking about the problem and carries with it the possibility of new targets and strategies for its blockade. The end is nowhere in sight but we are, at long last, making a significant beginning.

References

Ghajar, C.M. et al. (2013). The perivascular niche regulates breast tumour dormancy. Nature Cell Biology 15, 807–817.

Brabletz, T., Lyden, D., Steeg, P.S. and Werb, Z. (2013). Roadblocks to translational advances on metastasis research. Nature Medicine 19, 1104-1109.

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.

Fancy that?

Seeing as they started 28 years ago we can hardly blame members of the Harvard School of Public Health for publishing the results of their labours in tracking 120,000 people, asking them every few years what they’ve eaten and seeing what happened to them (a ‘prospective’ study). About one in five of the subjects died while this was going on but the message to emerge was that eating red meat contributes to cardiovascular disease, cancer and diabetes. The diabetes is non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes – about 90% of diabetes cases. The cancers weren’t specified, although the evidence for a dietary link is generally strongest for colon carcinoma. The risk is a little higher for processed red meat than unprocessed.

How much?

Massive, if you mean the amount of data they accumulated from such a huge sample size followed over many years. If you mean on a plate, their standard serving size was 85 grams (3 ounces) for unprocessed beef, pork or lamb) and 2 slices of bacon or a hot dog for processed red meat. One of those a day and your risk of dying from heart disease is increased by about 20 per cent and from cancer by about 10 per cent – and the risks are similar for men and women. Just to be clear, that is a daily consumption – and the authors very honestly acknowledge that ‘measurement errors inherent in dietary assessments were inevitable’. They also mentioned that one or two things other than steak can contribute to our demise.

Are we any wiser?

If you recall from Rasher Than I Thought? the risk of pancreatic cancer is increased by just under 20 per cent if you eat 50 grams of processed meat every day. This report suggests that a limit of 1.5 ounces (42 grams) a day of red meat (one large steak a week) could prevent around one in 10 early deaths. So does it tell us anything new? Not really. Was it worth doing? Yes, because it adds more solid data to that summarized in Are You Ready To Order?

And the message?

Unchanged. Do some exercise and eat a balanced diet – just in case you’ve forgotten, that means limit the amount of red meat (try fish, poultry, etc.), stick with the ‘good carbs’ (vegetables, fruits, whole grains, etc.), cut out the ‘bad’ (sugar – see Biting the Bitter Bullet), eat fishy fats not sat. fats and, to end on a technical note, don’t pig out.

 References

Pan A, Sun Q, Bernstein AM; et al. Red meat consumption and mortality: results from 2 prospective cohort studies [published online March 12, 2012]. Arch Intern Med. doi:10.1001/archinternmed.2011.2287.

Pan A, Sun Q, Bernstein AM; et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr. 2011;94(4):1088-1096.

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).