Taking Aim at Cancer’s Heart

 

Cancer is a unique paradox. At one level it’s as easy as can be to describe: damage to DNA (aka mutations) drives cells to behave abnormally — to make more of themselves when they shouldn’t.

But we all know that cancer’s fiendishly complicated — at least at the level of fine detail. Over the last decade or so the avalanche of sequenced DNA has revealed that every cell in a tumour is different: compare one cell to its neighbour and you’ll find variations in the individual units (the bases A, C, G & T) that make up the chains of DNA.

It’s a nightmare: every cancer is different so we need an infinite number of treatments to control or cure each one. Time to give up and retire to the pub.

Drivers and passengers

Not quite. DNA sequencing has also revealed that, amongst all the genetic mayhem, some mutations are more important than others. The movers and shakers have been dubbed ‘drivers’: those that come along for the ride are ‘passengers’. The hangers-on are heavily in the majority but, even so, several hundred drivers (i.e. mutated genes that give rise to abnormal proteins) have been identified. As it needs a group of drivers to work together to make a cancer we still have the problem that the number of critical combinations that can arise is essentially infinite.

One way of reducing the scale of the problem has been to look at what ‘driver’ proteins do in cells and to target those acting at key points to push cell proliferation beyond the normal.

Playing games

Just recently Giulio CaravagnaAndrea Sottoriva and colleagues at the Institute of Cancer Research, London and the University of Edinburgh have come up with a different approach. The idea goes back to the 1950s when a clever chap from Kansas by the name of Arthur Samuel came up with a program for IBM’s first commercial computer so that it could play draughts (checkers as our American friends call it) in its spare time. The program defined the patterns that could be formed by the pieces on the chequerboard so that, given enough of these, IBM 701 could indicate the optimal moves. Samuel called this machine learning, a precursor of the idea of artificial intelligence.

Perhaps the most famous moment in this saga came in 1997 when a later IBM computer, Deep Blue, beat the then world chess champion Garry Kasparov. Unsurprisingly, Kasparov was a bit miffed and accused IBM of cheating — to wit, getting a human to tell the machine what to do. Let’s hope that in the end he came to terms with the fact that Deep Blue could crank through 200 million positions per second and, however many games Grandmasters have in their heads, they can’t compete with that.

The cancer team realized that the mutations driving the evolution of cancer cells emerge as patterns in the sequence of DNA as a cell moves towards becoming independent of normal controls. Think of each cancer as a family tree of mutations, the key question being which branch leads to the most potent combination.

To pick out these patterns they applied a machine-learning approach known as transfer learning to the DNA sequences from a large number of cancers. They called this ‘repeated evolution in cancer’ — REVOLVER — aimed at picking out mutation patterns at the heart of cancer that foreshadow future genetic changes and can be used to predict how they will evolve.

Identifying patterns of mutation common to different tumours.

Samples are taken from different regions of a patient’s tumour (represented by the coloured dots). Their DNA sequences will have multiple variations that can mask underlying patterns of driver mutations present in some subgroups. The five trees show mutations picked up in those patients. REVOLVER uses transfer learning to screen the sequence data from many patients and pull out evolutionary trajectories shared by subgroups. The dotted red lines highlight common patterns that are represented in the lower strip. From Caravagna et al. 2018.

REVOLVER was applied to sequences from lung, breast, kidney and bowel cancers but there’s no reason it shouldn’t work with other tumours. The big attraction is that if these mini-sequence mutation patterns can be associated generally with how a given tumour develops they should help to inform treatment options and predict survival.

We have in the past referred to the ways cancers evolve as ‘genetic roulette’ — so perhaps it’s appropriate if game-playing computer programs turn out to be useful in teasing out behavioural clues.

Reference

Caravagna, G. et al. (2018). Detecting repeated cancer evolution from multi-region tumor sequencing data. Nature Methods 15, 707–714.

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Turning Ourselves On

 

It may seem a bit tasteless but we have to admit that cancer’s a very ‘trendy’ field. That is, there’s always a current fad — something for which either the media or cancer scientists themselves have the hots. Inevitable I suppose, given the importance of cancer to pretty well everyone and the fact that something’s always happening.

If you had to pick the front-running trends of late I guess most of us might go for ‘personalized medicine’ and ‘immunotherapy.’ The first means tailoring treatment to the individual patient, the second is boosting the innate power of the immune system to fight cancer.

Few things are trendier than this blog so it goes without saying that we’ve done endless pieces on these topics (e.g. Fantastic Stuff, Outsourcing the Immune Response, Self-Help – Part 2, bla, bla, bla).

How considerate then of Krijn Dijkstra, Hans Clevers, Emile Voest and colleagues from the Netherlands Cancer Institute to have neatly combined the two in their recent paper.

Simple really

What they did was did was easy — in principle. They grew fresh tumour tissue from patients in dishes in the laboratory. Although it doesn’t work every time, most of the main types of cancer have been grown in this way to give 3D cultures called tumour organoids — tumours-in-a-dish. That’s the ‘personalized’ bit.

Then they took blood from the patient and grew the lymphocytes therein in a dish to expand the T cells that were specific for the patient’s tumour. That’s the ‘‘immuno’ bit.

Growing tumour tissue (from non-small-cell lung cancer (NSCLC) and colorectal cancers [CRC] in culture as tumour organoids. This permits the expansion of T cells from peripheral blood to give an enlarged population of cells that will kill those tumours. From Dijkstra et al. 2018.

And the results?

They were able to show that enriched populations of tumour-reactive T cells could kill tumour organoids and, importantly, that organoids formed from healthy tissue were not attacked by these T cells.

Stained organoids (left) and original tissue (right) from two colorectal cancers (CRC-2 & CRC-5) showing how the organoids grow to have an architecture similar to the original tumour. From Dijkstra et al. 2018.

Their method worked for both bowel tumours and non-small-cell lung cancer but there’s no reason to suppose it can’t be extended to other types of cancer.

Some of their videos showing tumour organoids being chomped up by enriched killer T cells are quite dramatic. Cells labelled green that can be seen in this video are dying.

So there you have it: DIY tumour therapy!

Reference

Dijkstra, K.K. et al. (2018). Generation of Tumor-Reactive T Cells
by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids. Cell 174, 1–13.

Keeping Up With Cancer

 

Cancer enthusiasts will know that there are zillions of web sites giving info on cancer stats — incidence, mortality, etc. — around the world. Notable is the World Health Organization’s Globocan, an amazing compilation of data on all cancers from every country. The Global Burden of Disease Cancer Collaboration audits diagnosis rates and deaths for 29 types of cancer around the world each year. Needless to say, this too is a vast undertaking involving hundreds of scientists around the world. The organizing genius is Dr. Christina Fitzmaurice of the Institute for Health Metrics and Evaluation in the University of Washington, Seattle and, under her guidance, their update for 2016 has just come out.

What’s new?

In 2016 there were 17.2 million people diagnosed with cancer. 8.9 million died from cancers. By 2030 the number of new cancer cases per year is expected to reach 24 million. Well, you knew the numbers were going to be big — almost incomprehensibly so. But here’s the real shaker: the 17.2 M is 28% up on the 2006 figure — yes, that’s a rise of more than one quarter.

Yearly global cancer deaths from 1990 to 2016.

The green line is total deaths per 100,000 people.

Red line: Cancer death rates taking account of the increase in world population.

Blue line: Age-standardized death rates: these are corrected for population size and age structure. Age-standardization therefore gives a better indication of the prevalence and incidence of underlying cancer risk factors between countries and with time without the influence of demographic and population structure changes.

The numbers on the vertical axis are deaths per 100,000 people. From Our World in Data.

Any real surprises?

No. An increase of more than one quarter in cancer cases does indeed make you think but the grim numbers are only what you would predict from looking at the trends over the last 40 years. The graph shows death rates that, of course, reflect incidence. The total figure (top) shows starkly how the rise in the population of the world and our increasing life-span is steadily pushing up the overall cancer burden.

So it’s a mega-problem but the trends are smooth and gradual. There’s been no drastic upheaval.

Global trends

Yearly global cancer deaths from 1990 to 2016 for the four major cancer types.

The numbers on the vertical axis are age-standardized death rates per 100,000 people.

Because age-standardization assumes a constant population age & structure it permits comparisons between countries and over time without the effects of a changing age distribution within a population. From Our World in Data.

The global trends in deaths from the four major cancers look mildly encouraging (above). However, these should not cheer us up too much. In the developed world there are some positives. In the USA, for example, over the last 17 years deaths from prostate are down from 31.6 to 18.9, for breast from 26.6 to 20.3 and for lung from 55.4 to 40.6 per 100,000 people. For bowel cancer there’s been a slight increase (4.1 to 4.8).

In the wider world, however, the really dispiriting thing shown by the latest figures is that the increases in incidence and deaths are greatest in low- and middle-income countries.

What can we do?

Lung cancer (includes cancers of the trachea and bronchi) remains the world’s biggest cancer killer, accounting for 20% of all deaths in 2016. Over 90% of these were caused by tobacco. In the UK and the USA lung cancer deaths in men have markedly declined as a result of widespread smoking bans, as the graph below shows, and the female figures have started to show a sight decline.

Lung cancer deaths per 100,000 by sex from 1950 to 2002 for the UK and the USA. From Our World in Data.

Asia contributes over half the global burden of cancer but the incidence in Asia is about half that in North America. However, the ratio of cancer deaths to the number of new cancer cases in Asia is double that in North America. Although the leading cause of death world-wide is heart disease, in China it is cancer. Every year more than four million Chinese are diagnosed with the disease and nearly three million die from it. Overall, tobacco smoking is responsible for about one-quarter of all cancer deaths in China. Nevertheless, Chinese smoking rates continue to rise and air pollution in the major cities is fuelling the problem.

The under-developed world, however, continues to be targeted by the tobacco industry and the successful promotion of their products means that there is no end in sight to one of mankind’s more bizarre and revolting forms of self-destruction.

There are, of course, other things within our control that contribute significantly to the global cancer burden. If only we could give everyone clean water to drink, restrict our red meat and processed food consumption and control our exposure to uv in sunlight we would cut cancer by at least one half.

If only …

Reference

The Global Burden of Disease Cancer Collaboration (2018). Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. Published online June 2, 2018. doi:10.1001/jamaoncol.2018.2706.

No It Isn’t!

 

It’s great that newspapers carry the number of science items they do but, as regular readers will know, there’s nothing like the typical cancer headline to get me squawking ‘No it isn’t!” Step forward The Independent with the latest: “Major breakthrough in cancer care … groundbreaking international collaboration …”

Let’s be clear: the subject usually is interesting. In this case it certainly is and it deserves better headlines.

So what has happened?

A big flurry of research papers has just emerged from a joint project of the National Cancer Institute and the National Human Genome Research Institute to make something called The Cancer Genome Atlas (TCGA). This massive initiative is, of course, an offspring of the Human Genome Project, the first full sequencing of the 3,000 million base-pairs of human DNA, completed in 2003. The intervening 15 years have seen a technical revolution, perhaps unparalled in the history of science, such that now genomes can be sequenced in an hour or two for a few hundred dollars. TCGA began in 2006 with the aim of providing a genetic data-base for three cancer types: lung, ovarian, and glioblastoma. Such was its success that it soon expanded to a vast, comprehensive dataset of more than 11,000 cases across 33 tumor types, describing the variety of molecular changes that drive the cancers. The upshot is now being called the Pan-Cancer Atlas — PanCan Atlas, for short.

What do we need to know?

Fortunately not much of the humungous amounts of detail but the scheme below gives an inkling of the scale of this wonderful endeavour — it’s from a short, very readable summary by Carolyn Hutter and Jean Claude Zenklusen.

TCGA by numbers. The scale of the effort and output from The Cancer Genome Atlas. From Hutter and Zenklusen, 2018.

The first point is obvious: sequencing 11,000 paired tumour and normal tissue samples produced mind-boggling masses of data. 2.5 petabytes, in fact. If you have to think twice about your gigas and teras, 1 PB = 1,000,000,000,000,000 B, i.e. 1015 B or 1000 terabytes. A PB is sometimes called, apparently, a quadrillion — and, as the scheme helpfully notes, you’d need over 200,000 DVDs to store it.

The 33 different tumour types included all the common cancers (breast, bowel, lung, prostate, etc.) and 10 rare types.

The figure of seven data types refers to the variety of information accumulated in these studies (e.g., mutations that affect genes, epigenetic changes (DNA methylation), RNA and protein expression, duplication or deletion of stretches of DNA (copy number variation), etc.

After which it’s worth pausing for a moment to contemplate the effort and organization involved in collecting 11,000 paired samples, sequencing them and analyzing the output. It’s true that sequencing itself is now fairly routine, but that’s still an awful lot of experiments. But think for even longer about what’s gone into making some kind of sense of the monstrous amount of data generated.

And it’s important because?

The findings confirm a trend that has begun to emerge over the last few years, namely that the classification of cancers is being redefined. Traditionally they have been grouped on the basis of the tissue of origin (breast, bowel, etc.) but this will gradually be replaced by genetic grouping, reflecting the fact that seemingly unrelated cancers can be driven by common pathways.

The most encouraging thing to come out of the genetic changes driving these tumours is that for about half of them potential treatments are already available. That’s quite a surprise but it doesn’t mean that hitting those targets will actually work as anti-cancer strategies. Nevertheless, it’s a cheering point that the output of this phenomenal project may, as one of the papers noted, serve as a launching pad for real benefit in the not too distant future.

What should science journalists do to stop upsetting me?

Read the papers they comment on rather than simply relying on press releases, never use the words ‘breakthrough’ or ‘groundbreaking’ and grasp the point that science proceeds in very small steps, not always forward, governed by available methods. This work is quite staggering for it is on a scale that is close to unimaginable and, in the end, it will lead to treatments that will affect the lives of almost everyone — but it is just another example of science doing what science does.

References

Hutter, C. and Zenklusen, J.C. (2018). The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. Cell 173, 283–285.

Hoadley, K.A. et al. (2018). Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 173, 291–304.

Hoadley, K.A. et al. (2014). Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin. Cell 158, 929–944.

Hitchhiker Or Driver?

 

It’s a little while since we talked about what you might call our hidden self — the vast army of bugs that colonises our nooks and crannies, especially our intestines, and that is essential to our survival.

In Our Inner Self we noted that these little guys outnumber the human cells that make up the body by about ten to one. Actually that estimate has recently been revised — downwards you might be relieved to hear — to about 1.3 bacterial cells per human cell but it doesn’t really matter. They are a major part of what’s called the microbiome — a vast army of microorganisms that call our bodies home but on which we also depend for our very survival.

In our personal army there’s something like 700 different species of bacteria, with thirty or forty making up the majority. We upset them at our peril. Artificial sweeteners, widely used as food additives, can change the proportions of types of gut bacteria. Some antibiotics that kill off bacteria can make mice obese — and they probably do the same to us. Obese humans do indeed have reduced numbers of bugs and obesity itself is associated with increased cancer risk.

In it’s a small world we met two major bacterial sub-families, Bacteroidetes and Firmicutes, and noted that their levels appear to affect the development of liver and bowel cancers. Well, the Bs & Fs are still around you’ll be glad to know but in a recent piece of work the limelight has been taken by another bunch of Fs — a sub-group (i.e. related to the Bs & Fs) called Fusobacterium.

It’s been known for a few years that human colon cancers carry enriched levels of these bugs compared to non-cancerous colon tissues — suggesting, though not proving, that Fusobacteria may be pro-tumorigenic. In the latest, pretty amazing, installment Susan Bullman and colleagues from Harvard, Yale and Barcelona have shown that not merely is Fusobacterium part of the microbiome that colonises human colon cancers but that when these growths spread to distant sites (i.e. metastasise) the little Fs tag along for the ride! 

Bacteria in a primary human bowel tumour.  The arrows show tumour cells infected with Fusobacteria (red dots).

Bacteria in a liver metastasis of the same bowel tumour.  Though more difficult to see, the  red dot (arrow) marks the presence of bacteria from the original tumour. From Bullman et al., 2017.

In other words, when metastasis kicks in it’s not just the tumour cells that escape from the primary site but a whole community of host cells and bugs that sets sail on the high seas of the circulatory system.

But doesn’t that suggest that these bugs might be doing something to help the growth and spread of these tumours? And if so might that suggest that … of course it does and Bullman & Co did the experiment. They tried an antibiotic that kills Fusobacteria (metronidazole) to see if it had any effect on F–carrying tumours. Sure enough it reduced the number of bugs and slowed the growth of human tumour cells in mice.

Growth of human tumour cells in mice. The antibiotic metronidazole slows the growth of these tumour by about 30%. From Bullman et al., 2017.

We’re still a long way from a human therapy but it is quite a startling thought that antibiotics might one day find a place in the cancer drug cabinet.

Reference

Bullman, S. et al. (2017). Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science  358, 1443-1448. DOI: 10.1126/science.aal5240

Please … Not Another Helping

 

You may have seen the headlines of the: “Processed food, sugary cereals and sliced bread may contribute to cancer risk” ilk, as this recently published study (February 2018) was extensively covered in the media — the Times of London had a front page spread no less.

So I feel obliged to follow suit — albeit with a heavy heart: it’s one of those depressing exercises in which you’re sure you know the answer before you start.

Who dunnit?

It’s a mainly French study (well, it is about food) led by Thibault Fiolet, Mathilde Touvier and colleagues from the Sorbonne in Paris. It’s what’s called a prospective cohort study, meaning that a group of individuals, who in this case differed in what they ate, were followed over time to see if diet affected their risk of getting cancers and in particular whether it had any impact on breast, prostate or colorectal cancer. They started acquiring participants about 20 years ago and their report in the British Medical Journal summarized how nearly 105 thousand French adults got on consuming 3,300 (!) different food items between them, based on each person keeping 24 hour dietary records designed to record their usual consumption.

Foods were grouped according to degree of processing. The stuff under the spotlight is ‘ultra-processed’ — meaning that it has been chemically tinkered with to get rid of bugs, give it a long shelf-life, make it convenient to use, look good and taste palatable.

What makes a food ‘ultra-processed’ is worked out by something called the NOVA classification. I’ve included their categories at the end.

Relative contribution of each food group to ultra-processed food consumption in diet (from Fiolet et al. 2018).

And the result?

The first thing to be said is that this study is a massive labour of love. You need the huge number of over 100,000 cases even to begin to squeeze out statistically significant effects — so the team has put in a terrific amount of work.

After all the squeezing there emerged a marginal increase in risk of getting cancer in the ultra-processed food eaters and a similar slight increase specifically for breast cancer (the hazard ratios were 1.12 and 1.11 respectively). There was no significant link to prostate and colorectal cancers.

Which may mean something. But it’s hard to get excited, not merely because the effects described are small but more so because such studies are desperately fraught and the upshot familiar.

One problem is that they rely on individuals keeping accurate records. Another problem here is that the classification of ‘ultra-processed’ is somewhat arbitrary — and it’s also very broad — leaving one asking what the underlying cause might be: ‘is it sugar, fat or what?’ Furthermore, although the authors tried manfully to allow for factors like smoking and obesity, it’s impossible to do this with complete certainty. The authors themselves noted that, for example, they couldn’t allow for the effects of oral contraception.

The authors are quite right to point out that it is important to disentangle the facets of food processing that bear on our long-term health and that further studies are needed.

I would only add ‘rather you than me.’

Perforce in these pages we have gone on about diets good and bad so there is no need to regurgitate. Suffice to say that my advice on what to eat is the same as that of any other sane person and summarized in Dennis’s Pet Menace — and it’s not been remotely affected by this new research which, in effect, says ‘junk food is probably bad for you in the long run.’ But let’s leave the last word to Tom Sanders of King’s College London: “What people eat is an expression of their life-style in general, and may not be causatively linked to the risk of cancer.” 

Reference

Fiolet, T. et al. (2018). Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ 2018;360:k322 http://dx.doi.org/10.1136/bmj.k322

NOVA classification:

The ultra-processed food group is defined by opposition to the other NOVA groups: “unprocessed or minimally processed foods” (fresh, dried, ground, chilled, frozen, pasteurised, or fermented staple foods such as fruits, vegetables, pulses, rice, pasta, eggs, meat, fish, or milk), “processed culinary ingredients” (salt, vegetable oils, butter, sugar, and other substances extracted from foods and used in kitchens to transform unprocessed or minimally processed foods into culinary preparations), and “processed foods” (canned vegetables with added salt, sugar coated dried fruits, meat products preserved only by salting, cheeses, freshly made unpackaged breads, and other products manufactured with the addition of salt, sugar, or other substances of the “processed culinary ingredients” group).

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.

The answer to … everything is …

42, as all fans of Douglas Adams and The Hitchhiker’s Guide to the Galaxy will instantly tell you. In the years before he produced his best-seller, a chance contact with Footlights had drawn me into spending many merry evenings with Douglas in The Baron of Beef public house, more or less opposite St John’s College, where he was studying – sporadically, he would doubtless have said – English.

Had a piece of work that’s just come out in The British Medical Journal been published 40-odd years earlier I suspect I would have mentioned it at one of those gatherings – early on before rational thought took alcohol-fuelled flight. It’s interesting because it says we can put off dying from the things that kill most of us (heart failure and cancer) by what Jason Gill, Carlos Celis-Morales and their pals in the University of Glasgow call ‘active commuting’. By that they mean cycling to work is good. Physical inactivity (e.g., spending happy evenings in the pub) is bad.

Had I mentioned it, rather than coming up with an entirely whimsical response to the “ultimate question of life”, Douglas would have spotted that the key to hanging on to life is “on your bike”. Just think: if Jason & Chums had got a move on, history would have been changed. Pondering all their evidence over several pints of The Baron’s best, it’s hard to imagine Douglas coming up with any title other than The Biker’s Guide to the Galaxy.

But hang on: isn’t this just another pretty useless survey?

Maybe – but for several reasons it’s hard to write it off.

First, there have been quite a few studies over the years showing that cycling is good for you.

Second, this is one was huge – so more likely to be meaningful. Using the UK Biobank data it looked for links between death and the way in which more than a quarter of a million people got to work.

Third, and the thing that really caught my eye: the key finding stuck out like the proverbial sore thumb. Usually in surveys of things that might affect our health any trends are difficult to spot: eating X makes you live 10% longer or be 5% less likely to get Y … bla, bla, bla. But here you didn’t need to peer: cycling (a ‘long distance’) to work makes you 40% less likely to die – from anything!

Below is just one bit of their data: I’ve re-drawn it with the cycling result in red but it hardly needs that to highlight the difference between it, walking (blues) and the ‘non-actives’ (green: car or public transport). It’s true, a bit of biking can help (orange: mixed mode cycling) but the really clear benefit comes from cycling (lots) – though they don’t actually say how many miles per day counts as ‘long-distance cycling.’ Modes of transport and distances were self-reported and the latter just divided into ‘long’ and ‘short’.

How you get to work impacts your life expectancy. The figure shows the risk of death from all causes as hazard ratios (ratio of the hazard rates of death): the reference (hazard ratio 1) is travel by car or public transport (green). (From Celis-Morales, C. et al., 2017).

So what of heart failure and cancer?

Perhaps not surprisingly then, commuting by cycling was also associated with a markedly lower risk both of getting heart disease or cancer and of dying therefrom. To give one specific figure: cycling to work lowers the chance of developing cancer by 45%.

It can’t be the lycra

These are horrible studies to undertake, partly because they rely on human beings telling the truth but also because of what are called ‘confounding factors.’ For example, if someone plays a lot of sport and eats sensibly, you might guess they’d be relatively healthy, regardless of how they get to work. Conversely for smoking. However, Celis-Morales & Co did their best to allow for such things and therefore to come up with results that mean something.

But, if you take their findings at face value there remains a key question that the authors do not mention: what is it about biking that’s such a life-saver (assuming you don’t get knocked-off and squashed)? It’s a real puzzle because walking is generally held to be very good for you whilst cycling is the most energy-efficient means of transport devised by man. Both activities use nearly all of your muscles, albeit that biking really works out your glutes and quadriceps, but because bikes are so efficient you use less energy.

Counting the calories

You can do the sums – i.e. work out how many calories used walking, running or cycling on Wolfram Alfra. It’s just confirmed that my daily bike commute does indeed use about half the number of calories required for the same walk.

If you take your commute as training you would suppose that expending more energy (i.e. walking rather than biking) would strengthen your heart and cardiovascular system – and indeed this study shows commuters who did more than 6 miles a week at ‘typical walking pace of three miles an hour’ slightly lowered their risk of cardiovascular disease. But cycling was far more beneficial.

As to cancer, beyond the simplistic notion that fitness = strengthening your immune system and hence capacity resist abnormal cell growth, it’s hard to see a mechanism for biking being so much better than anything else.

So, never mind the science …

Away with Ford Prefect and latter-day variants, automotive  or otherwise! On your bike!! And if you can do it with a friend on a tandem, so much the better!!! Though if you’re going to do it à deux, it might be worth recalling that the Jatravartids had the wisdom to invent the aerosol deodorant before the wheel.

Reference

Celis-Morales, C. et al. (2017). Association between active commuting and incident cardiovascular disease, cancer, and mortality: prospective cohort study. British Medical Journal 357 doi: https://doi.org/10.1136/bmj.j1456

Pass the Aspirin

And so you should if you’ve got a headache – unless, of course, you prefer paracetamol. There can scarcely be anyone who hasn’t resorted to a dose of slightly modified salicylic acid (For the chemists: its hydroxyl group is converted into an ester group (R-OH → R-OCOCH3) in aspirin), given that the world gobbles up an estimated 40,000 tonnes of the stuff every year. It’s arguable, therefore, that an obscure clergyman by the name of Edward Stone has done more for human suffering than pretty well anyone, for it was he who, in 1763, made a powder from the bark of willow trees and discovered its wondrous property. The bark and leaves had actually been used for centuries – back at least to the time of Hippocrates – for reducing pain and fever, although it wasn’t until 1899 that Aspirin made its debut on the market and it was 1971 before John Vane discovered how it actually worked. He got a Nobel Prize for showing that it blocks production of things called prostaglandins that act a bit like hormones to regulate inflammation (for the chemists – again! – it irreversibly inactivates the enzyme cyclooxygenase, known as COX to its pals).

Daily pill popping

Aside from fixing the odd ache, over the years evidence has gradually accumulated that people at high risk of heart attack and those who have survived a heart attack should take a low-dose of aspirin every day. In addition to decreasing inflammation (by blocking prostaglandins) aspirin inhibits the formation of blood clots – so helping to prevent heart attack and stroke. Almost as a side-effect the studies that have lead to this being a firm recommendation have also shown that aspirin may reduce the risk of cancers, particularly of the bowel (colorectal cancer). Notably, Peter Rothwell and colleagues from Oxford showed that daily aspirin taken for 10 years reduced the risk of bowel cancer by 24% and also protected against oesophageal cancer – and a more recent analysis has broadly supported these findings. In addition they have also found that aspirin lowers the risk of cancers spreading around the body, i.e. forming distant metastases.

Why is aspirin giving us a headache – again?

First because a large amount of media coverage has been given to a report from Leiden University Medical Center, presented at The European Cancer Congress in September, that used Dutch records to see whether taking aspirin after being diagnosed with gastrointestinal cancer influenced survival. Their conclusion was that patients using aspirin after diagnosis doubled their survival chances compared with those who did not take aspirin. Needless to say, these words have been trumpeted by newspapers from The Times to the Daily Mail in the usual fashion (“Aspirin could almost double your chance of surviving cancer”). Unfortunately we can’t lay all the blame on the press: the authors of the report used the tactic of issuing a Press Release, a thoroughly reprehensible ploy for gaining attention when the work involved has not been peer reviewed. (The point here for non-scientists is that you can stand up at a meeting and say the moon’s made of blue cheese and it’s fine. Only after your work has been assessed by colleagues in the course of the normal publication process does it begin to have some credibility). So there’s a problem here, with what was an ‘observational study’, as to just what the findings mean – and the wise thing is to wait for the results of a ‘randomised controlled trial’ that is under way. 

The second source of mental strain is down to the ferociously named United States Preventive Services Task Force that has just (September 2015) come up with the recommendation that we should take aspirin to prevent bowel cancer. Why should we pay any attention? Because the ‘Force’ are appointed by the US Department of Health and they wield great influence upon medical practice – and because it’s the first time a major American medical organization has issued a broad recommendation to take aspirin to prevent a form of cancer.

In this latest oeuvre they confirm that the well-known risks attached to aspirin-eating (ulcers and stomach bleeding) are out-weighed by the protection against heart disease in those between the ages of 50 and 69 who are at high risk (e.g., have a history of heart attacks). If you feel your heart can take the strain you can find out your risk by using the National Heart, Lung, and Blood Institute’s online risk assessment tool. To get an answer you need to know your age, sex (i.e. gender, as its called these days), cholesterol levels (total and high density lipoproteins, HDLs – they’re the ‘good’ cholesterol), whether you smoke and your systolic blood pressure (that’s the X in X/Y).

This is such a critical issue it’s worth seeing what the Task Force actually said: “The USPSTF recommends low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults ages 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.”

If you’re younger than 50 or over 70 you’re on your own: the Force doesn’t recommend anything. And if you’re 60 to 69 the wording of their advice is wonderfully delicate: The decision to use low-dose aspirin to prevent CVD (cardiovascular disease) and colorectal cancer in adults ages 60 to 69 years who have a greater than 10% 10-year CVD risk should be an individual one.”

So that’s cleared that up …

Er, not quite. Various luminaries have been quick to demur. For example, Dr. Steven Nissen, the chairman of cardiology at the Cleveland Clinic has opined that the Task Force “has gotten it wrong.” In other words aspirin does more harm than good – though he might be a bit late as seemingly an astonishing 40% of Americans over the age of 50 take aspirin to prevent cardiovascular disease. I reckon that’s about 40 million people. Mmm … so that’s where the 40,000 tonnes goes (well, about one-fifth of it).

What’s the advice?

We’re more or less where we came in. I take an aspirin, or more usually a paracetamol, when I’ve got a stonking headache. Otherwise I wouldn’t take any kind of pill or supplement unless there is an overwhelming medical case for so doing. And pill-poppers out there might note the findings of Eva Saedder and her pals at Aarhus University that the single, strongest independent risk factor for drug-induced serious adverse events is the number of drugs that the patient is taking.

References

Rothwell, P. et al. (2012). Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials, Lancet DOI:1016/S0140-6736(11)61720-0

Rothwell P. et al. (2012). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trial, Lancet DOI:1016/S0140-6736(12)60209-8

Lancet editorial on Rothwell et al. 2011.

Algra, A. and Rothwell, P. (2012). Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials, Lancet Oncology DOI:10.1016/S1470-2045(12)70112-2.

Frouws M et al. Aspirin and gastro intestinal malignancies; improved survival not only in colorectal cancer? Conference abstract. European Cancer Congress 2015

Press release: Post diagnosis aspirin improves survival in all gastrointestinal cancers. The European Cancer Congress 2015. September 23 2015

Cuzick J, Thorat MA, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Annals of Oncology. Published online August 5 2014

U.S. Preventive Services Task Force Draft Recommendation Statement: Aspirin to Prevent Cardiovascular Disease and Cancer

Saedder, E.A. et al. (2015). Number of drugs most frequently found to be independent risk factors for serious adverse reactions: a systematic literature review. British Journal of Clinical Pharmacology 80, 808–817.

 

Bigger is Better

“Nonsense!” most males would cry, quite logically, given that we spend much of our time trying to persuade the opposite sex that size doesn’t matter. But we want to have it both ways: in the macho world of rugby one of the oldest adages is that ‘a good big ’un will always beat a good little ’un’.  Beethoven doubtless had a view about size – albeit unrecorded by history – but after he’d written his Eroica symphony, perhaps the greatest revolutionary musical composition of all, his next offering in the genre was the magical Fourth – scored for the smallest orchestra used in any of his symphonies. And on the theme of small can be good, the British Medical Journal, no less, has just told us that if we cut the size of food portions and put ’em on smaller plates we’ll eat less and not get fat!

Is bigger better?

Is bigger better?

All of which suggests that whether bigger is better depends on what you have in mind. Needless to say, in these pages what we have in mind is ‘Does it apply to cancer?’ – that is, because cancers arise from the accumulation in cells of DNA damage (mutations), it would seem obvious that the bigger an animal (i.e. the more cells it has) and the longer it lives the more likely it will be to get cancer.

Obvious but, this being cancer, also wrong.

Peto’s Paradox

The first person to put his finger on this point was Sir Richard Peto, most famous for his work with Sir Richard Doll on cancer epidemiology. It was Doll, together with Austin Bradford Hill, who produced statistical proof (in the British Doctors’ Study published in 1956) that tobacco smoking increased the risk of lung cancer. Peto joined forces with Doll in 1971 and they went on to show that tobacco, infections and diet between them cause three quarters of all cancers.

Whenever this topic comes up I’m tempted to give a plug to the unfortunate Fritz Lickint – long forgotten German physician – who was actually the first to publish evidence that linked smoking and lung cancer and who coined the term ‘passive smoking’ – all some 30 years before the Doll study. Lickint’s findings were avidly taken up by the Nazi party as they promoted Draconian anti-smoking measures – presumably driven by the fact that their leader, Gröfaz (to use the derogatory acronym by which he became known in Germany as the war progressed – from Größter Feldherr aller ZeitenGreatest Field Commander of all Time) was a confirmed non-smoker. Despite his usefulness, Lickint’s political views didn’t fit the ideology of the times. He lost his job, was conscripted, survived the war as a medical orderly and only then was able to resume his life as a doctor – albeit never receiving the credit he deserved.

Returning to Richard Peto, it was he who in 1975 pointed out that across different species the incidence of cancer doesn’t appear to be linked to the number of cells in animal – i.e. its size.   He based his notion on the comparison of mice with men – we have about 1000 times the number of cells in a mouse and typically live 30 times as long. So we should be about a million times more likely to get cancer – but in fact cancer incidence is another of those things where we’re pretty similar to our little furry friends. That’s Peto’s Paradox.

It doesn’t seem to apply within members of the same species, a number of surveys having shown that cancer incidence increases with height both for men and women. The Women’s Health Initiative found that a four inch increase in height raised overall cancer risk by 13% although for some forms (kidney, rectum, thyroid and blood) the risk went up by about 25%. A later study found a similar association for ovarian cancer: women who are 5ft 6in tall have a 23% greater risk than those who only make it to 5 feet. A similar risk links ovarian cancer to obesity (i.e. a rise in body mass index from 20 (slim) to 30 (slightly overweight) puts the risk up by 23%). Statistically sound though these results appear to be, it’s worth nothing that, as my colleague Paul Pharoah has pointed out, these risk changes are small. For example, the ovarian cancer finding translates to a lifetime risk of about 16-in-a-1000 for shorter women going up to 20-in-a-1000 as they rise by 6 inches.

It’s true that there may be a contribution from larger animals having bigger cells (whale red blood cells are about twice as big as those of the mouse) that divide more slowly but at most that effect seems small and doesn’t fully account for the fact that across species the association of size and age with cancer breaks down: Peto’s Paradox rules – humans are much more likely to get cancer than whales.

What did we know?

Well, since Peto picked up the problem, almost nothing about underlying causes. The ‘almost’ has been confined to the very small end of the scale and we’ve already met the star of the show – the naked mole rat – a rather shy chap with a very long lifespan (up to 30 years) but who never seems to get cancer. In that piece we described the glimmerings of an explanation but, thanks to Xiao Tian and colleagues of the University of Rochester, New York we now know that these bald burrowers make an extraordinarily large version of a polysaccharide (a polymer of sugars). These long strings of glucose-like molecules (called hyaluronan) form part of the extracellular matrix and regulate cell proliferation and migration. They’re enormous molecules with tens of thousands of sugars linked together but the naked mole rat makes versions about four times larger than those of mice or humans – and it seems that these extra-large sugar strings restrict cell behaviour and block the development of tumours.

Going up!

Our ignorance has just been further lifted with two heavyweight studies, one from Lisa Abegglen, Joshua Schiffman and chums from the University of Utah School of Medicine who went to the zoo (San Diego Zoo, in fact) and looked at 36 different mammalian species, ranging in size from the striped grass mouse (weighing in at 50 grams) to the elephant – at 4,800 kilogram nearly 100,000 times larger. They found no relationship between body size and cancer incidence, a result that conforms to Peto’s paradox. Comparing cancer mortality rates it transpires that the figure for elephants is less than 5% compared with the human range of 11% to 25%.

107 final pic

Cancer incidence across species by body size and lifespan. A selection of 20 of the 36 species studied is shown. Sizes range from the striped grass mouse to the elephant. As the risk of cancer depends on both the number of cells in the body and the number of years over which those cells can accumulate mutations, cancer incidence is plotted as a function of size (i.e. mass in grams × life span, years: y axis: log scale). Each species is represented by at least 10 animals (from Abegglen et al., 2015).

It can be seen at a glance that cancer incidence is not associated with mass and life span.

The Tasmanian devil stands out as a remarkable example of susceptibility to cancer through its transmission by biting and licking.

How does Jumbo do it?

In a different approach to Peto’s Paradox, Michael Sulak, Vincent Lynch and colleagues at the University of Chicago looked mainly at elephants – more specifically they used DNA sequencing to get at how the largest extant land mammal manages to be super-resistant to cancer. In particular they focused on the tumor suppressor gene P53 (aka TP53) because its expression is exquisitely sensitive to DNA damage and when it’s switched on the actions of the P53 protein buy time for the cell to repair the damage or, failing that, bring about the death of the cell. That’s as good an anti-cancer defence as you can imagine – hence P53’s appellation as the ‘guardian of the genome’. It turned out that elephants have no fewer than 20 copies of P53 in their genome, whereas humans and other mammals have only one (i.e. one copy per set of (23) chromosomes). DNA from frozen mammoths had 14 copies of P53 but manatees and the small furry hyraxes, the elephant’s closest living relatives, like humans have only one.

The Utah group confirmed that elephants have, in addition to one normal P53 gene, 19 extra P53 genes (they’re actually retrogenes – one type of the pseudogenes that we met in the preceding post) that have been acquired as the animals have expanded in size during evolution. Several of these extra versions of P53 were shown to be switched on (transcribed) and translated into proteins.

Consistent with their extra P53 fire-power, elephant cells committed P53-dependent suicide (programmed cell death, aka apoptosis) more frequently than human cells when exposed to DNA-damaging radiation. This suggests that elephant cells are rather better than human cells when it comes to killing themselves to avoid the risk of uncontrolled growth arising from defective DNA.

More genes anyone?

Those keen on jumping on technological bandwagons may wish to sign up for an extra P53 gene or two, courtesy of genetic engineering, so that bingo! – they’ll be free of cancers. Aside from the elephant, they may be encouraged by ‘super P53’ mice that were genetically altered to express one extra version of P53 that indeed significantly protected from cancer when compared with normal mice – and did so without any evident ill-effects.

We do not wish to dampen your enthusiasm but would be in dereliction of our duty is we did not add a serious health warning. We now know a lot about P53 – for example, that the P53 gene encodes at least 15 different proteins (isoforms), some of which do indeed protect against cancer – but there are some that appear to act as tumour promoters. In other words we know enough about P53 to realize that we simply haven’t a clue. So we really would be playing with fire if we started tinkering with our P53 gene complement – and to emphasise practicalities, as Mel Greaves has put it, we just don’t know how well the elephants’ defences would stack up if they smoked.

Nevertheless, on the bright side, light is at long last beginning to be shed on Peto’s Paradox and who knows where that will eventually lead us. Meanwhile Richard Peto’s activities have evolved in a different direction and he now helps to run a Thai restaurant in Oxford, a cuisine known for small things that pack a prodigious punch. Bit like Beethoven’s Fourth you could say.

a-gem-of-a-find-in-oxford

References

Peto, R. et al. (1975). Cancer and ageing in mice and men. British Journal of Cancer 32, 411-426.

Doll, R. and Peto, R. (1976). Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J. 2(6051):1525–36.

Maciak, S. and Michalak, P. (2015). “Cell size and cancer: A new solution to Peto’s paradox?”. Evolutionary Applications 8: 2.

Doll, R. and Hill, A.B. (1954). “The mortality of doctors in relation to their smoking habits”. BMJ 328 (7455): 1529.

Doll, R. and Hill, A.B. (November 1956). “Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors”. British Medical Journal 2 (5001): 1071–1081.

Tian, X. et al. (2013). High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346-349.

Abegglen, L.M., Schiffman, J.D. et al. (2015). Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. doi:10.1001/jama.2015.13134.

Sulak, M., Lindsey Fong, Katelyn Mika, Sravanthi Chigurupati, Lisa Yon, Nigel P. Mongan, Richard D. Emes, Vincent J. Lynch, V.J. (2015). TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants. doi: http://dx.doi.org/10.1101/028522.

García-Cao, I. et al. (2002). ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO Journal 21, 6225–6235.