Holiday Reading (4) – Can We Make Resistance Futile?

For those with a fondness for happy endings we should note that, despite the shortcomings of available drugs, the prospects for patients with a range of cancers have increased significantly over the latter part of the twentieth century. The overall 5-year survival rate for white Americans diagnosed between 1996 and 2004 with breast cancer was 91%; for prostate cancer and non-Hodgkin’s lymphoma the figures were 99% and 66%, respectively. These figures are part of a long-term trend of increasingly effective cancer treatment and there is no doubt that the advances in chemotherapy summarised in the earlier Holiday Readings are contributory factor. Nonetheless, the precise contribution of drug treatments remains controversial and impossible to disentangle quantitatively from other significant factors, notably earlier detection and improved surgical and radiotherapeutic methods.

Peering into the future there is no question that the gradual introduction of new anti-cancer drugs will continue and that those coming into use will be more specific and therefore less unpleasant to use. By developing combinations of drugs that can simultaneously poke the blancmange at several points it may be possible to confront tumor cells with a multiple challenge that even their nimbleness can’t evade, thereby eliminating the problem of drug resistance. Perhaps, therefore, in 20 years time we will have a drug cabinet sufficiently well stocked with cocktails that the major cancers can be tackled at key stages in their evolution, as defined by their genetic signature.

However, on the cautionary side we should note that in the limited number of studies thus far the effect of drug combinations on remission times has not been startling, being measured in months rather than years or decades. Having noted the durability of cancer cells we should not be surprised by this and the concern, of course, is that, however ingenious our efforts to develop drug cocktails, we may always come second to the adaptability of nature.

Equally perturbing is the fact that over 90% of cancer deaths arise from primary tumors spreading to other sites around the body. For this phenomenon, called metastasis, there are currently very few treatment options available and the magnitude of this problem is reflected in the fact that for metastatic breast cancer there has been little change in the survival rates over the past forty years.

Metastasis therefore remains one of the key cancer challenges. It’s over 125 years since the London physician Stepen Paget asked the critical question: ‘What is it that allows tumour cells to spread around the body?’ and it’s a daunting fact that only very recently have we made much progress towards an answer – and thus perhaps a way of controlling it. To the fore in this pursuit has been David Lyden and his colleagues at Weill Cornell Medical College in New York. Their most astonishing finding is that cells in the primary tumour release messengers into the circulation and these, in effect, tag what will become landing points for wandering cells. Astonishing because it means that these sites are determined before any tumour cells actually set foot outside the confines of the primary tumour. Lyden has christened this ‘bookmarking’ cancer. That is a quite remarkable finding – but, as ever in science, it merely shifts the question to ‘OK but what’s the messenger?’

A ray of sunshine

It might appear somewhat churlish, especially after all that funding, to end on a note of defeatist gloom so let’s finish with my ray of sunshine that represents a radical approach to the problem. It relies on the fact that small numbers of cells break away from tumors and pass into the circulation. In addition, tumours can release both DNA and small sacs – like little cells – that contain DNA, proteins and RNAs (nucleic acids closely related to DNA). These small, secreted vesicles are called exosomes – a special form of messengers, communicating with other cells by fusing to them. By transferring molecules between cells, exosomes may play a role in mediating the immune response and they are now recognized as key regulators of tumour growth and metastasis.

Step forward Lyden and friends once more who have just shown in a mouse model of pancreatic cancer that exosomes found their way to the liver during the tumour’s earliest stages. Exosomes are taken up by some of the liver cells and this sets off a chain of cell-to-cell signals that eventually cause the accumulation of a kind of molecular glue (fibronectin). This is the critical ingredient in a microenvironment that attracts tumour cells and promotes their growth as a metastasis (secondary growth). So you can think of exosomes as a kind of environmental educator.

Exosome Fig

Exosomes released from primary tumours can mark a niche for metastasis.

The small sacs of goodies called exosomes are carried to the liver where they fuse with some cells, setting off a chain reaction that produces a sticky protein – fibronectin – a kind of glue for immune cells and tumour cells. (from Costa-Silva, B., Lyden, D. et al., Nature Cell Biology 17, 816–826, 2015).

The recent, remarkable technical advances that permit the isolation of exosomes also make it possible to fish out circulating tumour cells and tumour DNA from a mere teaspoonful of blood.

Circulating tumour cells have already been used to monitor patient responses to chemotherapy – when a treatment works the numbers drop: a gradual rise is the earliest indicator of the treatment failing. Even more exciting, this approach offers the possibility of detecting the presence of cancers years, perhaps decades, earlier than can presently be achieved. Coupling this to the capacity to sequence the DNA of the isolated cells to yield a genetic signature of the individual tumor can provide the basis for drug treatment. There are still considerable reservations attached to this approach but if it does drastically shift the stage at which we can detect tumors it may also transpire that their more naïve forms, in which fewer mutations have accumulated, are more susceptible to inhibitory drugs. If that were to be the case then even our currently rather bare, though slowly expanding, drug cabinet may turn out to be quite powerful.

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.