Clocking In With Cancer Treatment

I always hesitate to say things like ‘you may recall’ as, from much undergraduate teaching, I’ve learned that blithe throwaways like ‘you’ll remember this from last Monday’s lecture’ tend to be met with blank stares and trying ‘you met this idea in the first year’ on second year classes will draw forth outright mirth blending with mutinous howls. So let’s just start by noting that three weeks ago in Our Inner Self we had a march-past of our intestinal army of bacteria and saw that it is in continuous flux, its make-up oscillating in time to our biological clock – the daily variation that governs most of our bodily functions including the sleep-wake cycle. That’s amazing stuff but a sharp bit of lateral thinking raises interesting questions. If most of the important things in our bodies tick to circadian rhythms, is cell proliferation one of them – after all, the process of cells making more of themselves is at the heart of life. Answer ‘yes.’ But, as abnormal cell proliferation – i.e. something going wrong – is a perfectly adequate three-word definition of cancer, a small step extends the question to ‘do tumours also have rhythm?’ Answer, again, ‘yes.’ A little background before we explain.

Turning back to the clock

In Twenty more winks we saw that there’s a connection between sleep (or rather lack of it) and cancer and showed how two pairs of genes (CRY/PER and CLOCK/BMAL1) lie at the core of circadian timekeeping. They control the sleep-wake cycle and much else. The proteins they make form an orchestrated feedback loop, synchronised by light-induced signalling. That is, the expression of each pair oscillates with a period of roughly 24 hours, but the pairs are out of step to the tune of about 12 hours. The proteins encoded by these genes regulate the expression of many other genes that ensure the cells and tissues of the body beat to an appropriate rhythm. Many messengers spread circadian oscillations around the body via the blood of which, in humans, cortisol (made by the adrenal glands) is perhaps the most familiar (it’s a steroid hormone: the medication dexamethasone is cortisol with two small, extra bits that make it 25 times more potent). You can fairly easily measure cortisol concentration in blood and you’d expect to find that at nine in the morning you’d have roughly double your midnight amount. In other words cortisol is part of your wake-up call. It turns on your appetite, gets you geared up for physical activity and it also activates anti-stress and anti-inflammatory signal pathways. EGFR & cortisol Cross-talk between EGFR and cortisol during the active phase (right: high cortisol) and the resting phase (left: low cortisol). (from Lauriola et al., 2014).

Getting the message across

Taking the memory-prodding risk yet again, in Mission Impossible? we described how biological signals from the outside world bind to receptors (proteins) to convey their message (I’m here, do something!) to the interior of cells. So the picture is: cells receive many signals from messengers that, one way or another, talk to the nucleus, switching on genes that drive proliferation. Most external messengers are proteins themselves – one example is a potent growth promoter called epidermal growth factor (EGF) that works by switching on the EGF receptor (EGFR). Cortisol isn’t a protein: as we’ve noted, it’s a steroid – which means it can diffuse across membranes – but, once inside a cell it works in essentially the same way, by binding to its specific receptor. The upshot of all this is that messengers transmit information from outside the cell to the nucleus – where DNA lives, the cells’ repository of genetic material – so that genes become activated to produce proteins.

Oscillating signals: cellular chattering

The picture of multiple, linear signalling pathways co-existing within cells invites the idea that their protein components might be unable to resist tapping in to their neighbours’ conversations – and so it has turned out. However, for pathways like the EGFR that signal cell growth, cross-talk with cortisol signalling is more than merely listening in. Proteins activated by the steroid hormone can actually interfere with the relays in the EGFR pathway so that EGF signals are suppressed during the active phase (day-time in us, night-time in rodents) but enhanced during the resting phase.

The meaning for life

So growth signaling is under circadian control – by and large our cells do their multiplying when we are at rest. Interesting although perhaps not unexpected. But, as The Bonzo Dog Doo-Dah Band warbled, ‘here comes the twist’ (Urban Spaceman, 1968 if you’re struggling). These pathways are the very ones that are hyper-activated (i.e. mutated) to drive cancer cells to make more of themselves and they are, accordingly, the targets for many anti-cancer drugs. However, chemotherapy is usually administered as single bursts, at daily or longer intervals, and drugs are progressively removed by metabolism thereafter. This means that much of the impact may be lost if, when the drug concentration is at its highest, the target pathway is already suppressed by high glucocorticoids . There’s evidence consistent with this idea from animals bearing EGFR-driven tumours treated with specific inhibitors that are more effective if administered in the resting phase rather than in the active phase.

It’s all in the timing

So two new messages are now making themselves heard in the world of cancer biology. The first is beginning to tell the full story of clock complexity. The second takes up this theme by pointing out that a circadian clock-based model in cancer therapy may offer improved methods for prevention and treatment.


Lauriola, M. et al. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nat. Commun. 5:5073 doi: 10.1038/ncomms6073 (2014).


Beware of Greeks …

Finding the words

One of the pitfalls of writing is repetition. Be it book, blog or broadsheet, most authors must dread someone gleefully chirruping ‘You used that exact phrase in 1999.’ I wonder if The Immortal Bard suffered likewise – having to resort to ferreting through piles of dusty manuscripts, finally in desperation shouting ‘Anne, Anne – got this great new line If you prick us do we not bleed? – Heard it before?’

‘Yes, of course dear. You used it in that thing about the Italian moneylender.’

‘Damn. Thought it sounded familiar. Where would I be without your memory – make me immortal with a kiss.’

‘Give over you daft beggar – even you know that’s one of that Marlowe bloke’s lines!’


I’m something of a sitting duck here, partly through not being Shakespeare but also because of the habit of often talking about biology. Take one simple example, Will’s tiny pinprick of blood – in which there will be about fifty million cells. That’s fifty million separate little sacs swirling around in a bead you wouldn’t notice if it wasn’t bright red. Isn’t that stunning for starters? Indeed, but it’s when we turn to molecular cancer that nature’s capacity to amaze is unfettered, the remarkable becomes the norm and even the English language can seem inadequate.

Finding the exit

A study of a mouse model of one form of leukemia is the most recent contribution to have us sifting Shakespeare’s superlatives to do justice to the discovery. Blood cells start life within the bone marrow but, until they’ve matured, they’re corralled by a marrow–circulation barrier, also made of cells. Adult cells normally make proteins on their surface that attach to the barrier, and these help them to squeeze past into the freedom of the circulation. In leukemia abnormal levels of white blood cells are present in the circulation, which means that those cells have also found a way through the bone barrier. A Prague group have shown that one type of leukemic cell has come up with an astonishingly novel escape mechanism in which they release fragments of their own DNA. That’s pretty staggering because not only is DNA generally locked in the nucleus but it comes in large chunks called chromosomes. So two very unusual things have happened to get to this stage: (1) some of DNA has been shattered and (2) these pieces have crossed not only the membrane that encloses the nucleus but also the outer boundary of the cell itself.

DNA fragments from tumour cells enter barrier cells and kill them, releasing tumour cells into the circulation

DNA fragments from tumour cells enter barrier cells and kill them, releasing tumour cells into the circulation

But then something even more extraordinary happens: having tunneled their way out of the tumour cell, the escaped bits of DNA do a kind of reverse reprise by entering the cells that form the barrier between bone marrow and circulating blood. It’s as though the barrier cells see the passing packages of DNA as presents and gobble them up. Alas! They should have read their Virgil – or at least Dryden’s summary of the tale of the wooden horse of Troy: ‘Trust not their presents, nor admit the horse’ – for the barrier cells pay the ultimate price for their gluttony. The DNA fragments are sensed as something abnormal – as indeed they are – and this provokes a stress response – and a pretty extreme one at that – because the cells are so overwhelmed by the influx that they commit suicide.

The capacity for individual cells to switch on a death program is an important part of life – it’s essential in normal development and it’s also the best cancer defence we have. In other words, if things get out of control, kill the cell – because that eliminates the danger and cells can be replaced. But here we have an almost stupefying paradox: in the tumour cells this defence is neutralized – but they’ve come up with a way of turning it on in the normal cells they have to get past in order to spread around the organism.

It’s another astounding example of the plasticity of our genetic material and the incredible adaptability of cancer cells. Even Mr. S. might feel adjectivally challenged!


Dvořáková, M. et al., (2012). DNA released by leukemic cells contributes to the disruption of the bone marrow microenvironment. Oncogene 10 December 2012; doi: 10.1038/onc.2012.553