Trouble With The Neighbours

It may seem odd to the point of negligence that a problem mankind has been grappling with since at least the time of the ancient Egyptians should, within the last ten years or so, be shown to have a whole new dimension, scarcely conceived hitherto. This hidden world, often now called the tumour microenvironment, is created as solid tumours develop and attract a variety of normal cells from the host to form a cellular cloud that envelops them and supports their growth (as we noted in Cooperative Cancer Groupies). We shouldn’t beat ourselves up for being slow to grasp its existence yet alone its importance – just take it as a reminder of the multi-faceted complexity that is cancer.

It’s true that over one hundred years ago the London physician Stephen Paget came up with his “seed and soil” idea – the notion that when cells escape from a primary tumour and spread to secondary sites (metastasis) they need to find a suitable spot that will nourish their growth, otherwise they perish – a fate that befalls most of them, fortunately for us.

But in the twenty-first century …

Perceptive though that idea was, it didn’t relate to the goings on in the vicinity of primary tumours – where the current picture is indeed of a cosmopolitan crowd of cellular groupies being recruited as the tumor starts to grow such that they infiltrate and closely interact with the cancer cells. The groupies are attracted by chemical messengers released by tumour cells – but it becomes a two-way communication, with messenger proteins shuttling to and fro between the different cell types.

Tumor uenvirThe tumour neighbourhood.

Two-way communication between host cells and tumor cells.

 White blood cells (e.g., lymphocytes and macrophages) are one group that succumbs to the magnetism of tumours. They’re part of the immune response that initially tries to eliminate the abnormal growth but, in an extraordinary transformation, when tumour cells manage to evade this defense the recruited cells change sides so to speak, switching their action to release signals that actively support tumor growth. The idea of boosting the initial anti-tumour response, thereby using the host defence system to increase the efficiency of tumour elimination, is the basis of immunotherapy, a popular research field at present to which we will return in a later piece.

Who’s who among the groupies

The finding that cells flooding into the ambience of a tumour can affect growth of the cancer has focussed attention on identifying all the constituents of the cellular cloud and unraveling their actions. Two recent studies by Claudio Isella from the University of Turin and Alexandre Calon from Barcelona, with their colleagues, have looked at a type of bowel cancer that has a particularly poor prognosis and used an ingenious ploy to lift the veil on who’s doing what to whom in the tumour milieu.

The tumours were initially classified on the basis of a genetic signature – that is, a snapshot of which genes are active in a tumour sample – ‘switched on’ or ‘expressed’ in the jargon – meaning that the information encoded in a stretch of DNA sequence is being used to make a functional gene product, usually a protein. They then used the crafty tactic of implanting human tumour cells into mice (the mice are ‘immunocompromised’ so that they don’t reject the human cells), separated the major types of cell in the tumours that grew and then looked at the genes expressed in those sub-sets. Remarkably, it emerged that, of the cell groupies that infiltrate into primary tumours, fibroblasts are particularly potent at driving tumour growth and metastasis. Fibroblasts are a cell type that makes the molecular scaffold that gives structure and shape to the various tissues and organs in animals – so it’s a surprise, to say the least, to find that cells with a rather mundane day job can play an important role in cancer progression. In this model system the sequence differences between corresponding human and mouse genes confirm that the predominant driver is mouse cells infiltrating the human tumours. Perhaps it shouldn’t be quite such a shock to find fibroblasts dabbling in cancer as we have met cancer-associated fibroblasts (CAFs) before as cells that, by releasing leptin, can promote the growth and invasion of breast cancer cells (in Isn’t Science Wonderful? Obesity Talks to Cancer).

How useful might this be?

As ever, this is just one more small step. However, the other key finding from this work is that a critical signal for the CAFs is a protein called transforming growth factor beta (TGFβ) and a small molecule that blocks its signal inhibits metastasis of human tumour cells in the mouse model. So yet again the cancer biologist’s best friend gives a glimmering of hope for human therapy.

References

Isella, C. et al. (2015). Stromal contribution to the colorectal cancer transcriptome. Nature Genet. http://dx.doi.org/10.1038/ng.3224

Calon, A. et al. (2015). Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nature Genet. http://dx.doi.org/10.1038/ng.3225

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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”

Twenty winks

Not now obviously but after you’ve read the first episode of this absorbing tale you may feel a nap is in order, despite the fact that in Wake up at the back we noted that snoring can give you cancer.

Setting aside that hazard, the general finding is that most people require seven or eight hours of sleep to function optimally. Fall short of that, to less than six hours even for one night, and we all know that the consequences may include a degree of grumpiness helped along by a tendency to clumsiness and generally heightened incompetence. If you happen to suffer from hypertension you could measure another result because your blood pressure will be even higher than usual for the rest of the day. However, these are all reversible states, so that real problems only come with more extended sleep deprivation and there is much evidence that this can profoundly affect memory, creativity and emotional stability, as well as leading to heart disease, diabetes and obesity. The molecular drive for the latter is that folk who are short of sleep have lower levels of the hormone leptin (which tells the brain you’ve had enough to eat) but higher levels of ghrelin (appetite stimulant). One week of only four hours nightly kip converts healthy young men to pre-diabetics in terms of their insulin and blood sugar levels.

The cancer link

To all of which must be added the dribble of reports over many years that disrupted sleep patterns, such as result from shift-work, may increase the risk of a variety of cancers (these include breast, prostate, bowel and endometrial cancers and also non-Hodgkin’s lymphoma). The effects are moderate (that is, the risk rise is small – typically up to 20%), making these findings suggestive rather than conclusive, although they are bolstered by a considerable number of studies on animals. So sleep, or rather lack of it, is yet another of these things that seems to affect cancer but for which really hard evidence is lacking. It’s not a9f5f190difficult to see why. You can’t put a number on ‘a good night’s sleep’ (though you can now get phone apps that record your every snort and contortion) nor do we understand the biological consequences of sleep disruption, and then there are the perpetual problems that everyone’s different and cancers take years to show themselves. However, you can put a figure on how you feel about sleep: our friends at the wonderful Karolinska Institute in Stockholm have come up with a Sleepiness Scale (1 = very alert, 9 = very sleepy, great effort to keep awake) – which could replace the traditional grunt when asked ‘How are you?’ ‘Oh, much as usual, about eight on the Karolinska Scale.’

Sleeping Off Breast Cancer

Trawling the literature it seems that the majority of cancer/sleep studies focus on the breast and a word about two of the most recent will suffice to paint the picture. In a large group of Japanese ladies over the age of 40 those who said they slept for less than six hours were markedly more likely to develop breast cancer than those who slept longer. Over nine hours a night (sleep that is) even appeared to give a degree of protection.

The main culprit for the breast cancer/sleep link is shift work, illustrated by the Danish military where women working night-shifts are more prone to breast cancer than those with normal sleep patterns and there is an upward trend in risk with years of night-shift work.

An association with ovarian cancer has also been reported although, somewhat perplexingly, that study didn’t show that the risk got bigger the longer night-shifts were worked. This rather confusing picture may reflect individual variation. As we all know, some folk are ‘larks’ – up at the crack of dawn – my lady wife is one – whereas others are ‘owls’ who perform better the later it is (no prize for guessing what kind of bird I am – bit of domestic incompatibility there!). It may be that ‘owls’ suffer less from night-shift perturbation and they may therefore be more likely to opt for that mode of work – and indeed the Danish study found that ‘larks’ on night-shifts were more likely to get breast cancer. As if that’s not enough, irregular shift patterns make it more difficult for women to conceive and working only nights increases the chances of miscarrying.

Similar results have been found for other cancers, notably of the bowel – 50% more likely to occur in those who sleep an average of less than six hours a night than those who zzzz for over seven. Put another way, the less than six hours risk is about the same as having a first degree relative with the disease or eating lots of red meat – and similar to that for breast cancer.

Mu Treadmill

th-2

th-1

Mice Sleep Too

It’s not a bad idea to keep in mind that we are very similar to mice – we’ve got more or less the same number of genes and exercising (on a treadmill for example) helps to keep at least some cancers at bay. Another similarity is that sleep deprivation upsets the works so that, for example, in models of colon cancer it reverses the beneficial effects of moderate exercise.

So insomnia is no laughing matter, however it comes about, and next time we’ll put two and two together by looking at the molecular story – after which you really may need forty winks.

 References

Kakizaki, M. et al. (2008).  Sleep duration and the risk of breast cancer: the Ohsaki Cohort Study. Br J Cancer  99, 1502–1505.

Hansen, J. and Lassen, C.F. (2012). Nested case-control study of night shift work and breast cancer risk among women in the Danish military. Occup Environ Med., 69, 551–556.

Bhatti, P. et al. (2012). Nightshift work and risk of ovarian cancer. Occup Environ Med., 0:1–7. doi:10.1136/oemed-2012-101146.

Thompson, C.L. et al. (2011). Short Duration of Sleep Increases Risk of Colorectal Adenoma. Cancer 117, 841–847.

Zielinski, M.R. et al. (2012). Influence of chronic moderate sleep restriction and exercise on inflammation and carcinogenesis in mice. Brain, Behavior, and Immunity 26, 672–679.

Isn’t Science Wonderful? Obesity Talks to Cancer

A couple of week’s ago we looked at how being obese can give cancer a helping hand. I thought this would be useful as most people know there is a link but perhaps not much more than that. The message had two simple parts: (1) When we make extra fat cells they change the metabolism of our bodies through chemical signals that wander around and, in passing, can also drive cancer growth, and (2) Some of the extra fat cells congregate around tumours and give them direct positive vibes (i.e. other, local chemical signals).

But you may have spotted that I didn’t actually say what these ‘signals’ are – for the very good reason that we know rather little about them. Step forward, right on cue, Ines Barone, Suzanne Fuqua and friends from the University of Calabria and Baylor College of Medicine, Houston with a wonderful paper that’s just been published. Wonderful because it’s got so much data I’m green with envy but also because, like most excellent science papers, the key message is simple: normal cells that have moved into the neighbourhood can indeed talk directly to tumour cells. And the messenger is … leptin!

That’s astonishing. Even those with only a smattering of knowledge about how we work will know that leptin plays a key role in regulating energy balance. It’s a protein – a hormone – that circulates in our blood at levels roughly proportional to body fat. Its job is to signal the ‘full’ state, i.e. to reduce appetite. Somewhat perversely, obesity usually causes abnormally high leptin levels but it doesn’t work very well because the body has become resistant to its signal – much as happens with insulin in type 2 diabetes.

The new results show that leptin, released from nearby cells, can bind to cancer cells and make them do two things: (1) Release a chemical that tells the adjacent cells to send out even more leptin, and (2) Make proteins that help the tumour cells grow and invade.

There are a few wrinkles to these results. The study was on breast cancer cells with a particular mutation (in a receptor for the hormone estrogen) and the ‘groupies’ providing the leptin turned out not to be fat cells but fibroblasts – part of the supportive framework of cells and tissues – so they’re ‘cancer-associated fibroblasts’ (CAFs). And when the CAFs release leptin it floods out and the tumour cells embrace it and make yet more receptors for leptin to bind to on their surface.

But these details matter less than the key point: for at least some types of cancer cell a hormone often made in excessive amounts in obesity can signal directly to tumour cells, telling them to grow and spread. This doesn’t mean that all breast tumours, yet alone all cancers, respond to leptin. What it does show is that a key factor in obesity can talk directly to some types of tumour cell. It’s another example of the painstaking way in which science usually proceeds and, assuming the results are reproducible, we have one more little bit of the jig-saw.

Reference

Barone, I., Catalano, S., Gelsomino, L. et al. (2012). Leptin Mediates Tumor−Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells. Cancer Research 72, 1416-1427.