Cancer Genetics: Never Black or White

The National Heath Service occupies a uniquely revered place in the psyche of the British people – as indeed it should, the concept of free, first rate health care available when required being one of the hallmarks of civilization. Founded in 1948, the NHS has continued to this day to fulfill its remit with astonishing efficiency in the face of demands beyond comprehension sixty years ago, as both the size of the population and life expectancy have increased and medical practice has been transformed by technical advances. Even so, there is one area in which there is a surprising shortfall in the performance of the NHS when compared with most other European countries or with the USA – cancer survival rates.

We’re behind you!!

Broadly speaking, the latest findings of a massive study (called CONCORD-2, a long-term global comparison of cancer survival) show 5-year cancer survival rates in the UK for 2005 to 2009 to have been worse than they were in many European countries at least a decade earlier. “Shameful” cried Macmillan Cancer Support – rarely a helpful response but you have to concede it’s scarcely grounds for an outbreak of British smugness. More to the point, Cancer Research UK insisted the gulf was often linked to deprivation, i.e. patients in poorer areas tend to live unhealthy lifestyles so they are more susceptible and likely to be diagnosed later. This refers to what has become known as the postcode (zipcode) lottery whereby the chances of being diagnosed early and surviving various forms of cancer differ significantly (meaning as much as two-fold!) across the UK. Further contributions come from general practitioners missing the early signs of cancer, adding to the delay in referral, together with variable standards of treatment.

And the answer is?

But hang on! None of this actually explains why these problems should be more acute in the UK than in, say, France or Finland who presumably have their share of the poor and incompetent. So what might be different in the UK? Here’s my theory. Maybe it’s just us, the Jane & John Does lining up to become cancer patients. Dentists reckon they can pick Brits from Yanks just by peering into their oral cavities (Brits have cavities {ho ho} whereas Americans are perfect – tooth-wise that is). Why? Because we don’t care: we figure our bodies are non-maintenance machines – so we never dream of getting them serviced, that is, having regular check-ups – and when they do conk out we expect the wondrous NHS to fix it. To see if there’s any truth in this theory I conducted a meaningless, random poll in my department (featuring two Americans, one Finn, a Dutchman, two German ladies and a French girl – all from nations that do better than the UK) asking ‘how health aware are your countrymen compared with the British?’ Result? They’re all hypochondriacs compared to Brits whose default method is to avoid doctors until they’re at death’s door. So there we have it: it’s our fault and if we just looked after ourselves a bit better the UK would scrabble its way up the cancer survival league.

Sounds familiar?

Take the specific example of breast cancer. 81% of UK women diagnosed between 2005 and 2009 were alive five years later but in Sweden, France and Italy the rates range from 86 to 87%. This kind of gap is reminiscent of that in the USA between African American women and those of European descent – presently 79% versus 92 % – a disparity that has remained pretty constant over the last 40 years even though the survival rates of both groups have steadily risen (the overall USA survival rate for breast cancer is now 89%). Again the divide has been attributed to poverty and education level, together with lack of health insurance, so that detection is delayed and survival times shortened.

So it’s clear that multiple factors contribute to the variable treatment success rates but so far there’s no evidence that genetic differences play a part, for example, by giving rise to more aggressive forms of cancer.

A little more light in one corner

Breast cancers are an enormously varied set of diseases and as such they’re a challenge even to classify yet alone to treat. The recent rapid progress in DNA sequencing has led to a new genome-based classification system but there is still strong reliance on the traditional prognostic and predictive factors, notably what’s called hormonal status – meaning presence on the surface of the tumour cells of the protein receptors to which the hormones oestrogen and progesterone attach, together with the presence or otherwise of the human epidermal growth factor receptor 2 (HER2). One significant sub-group has no detectable levels of these proteins – they’re ‘triple negative’ – and they make up 10-15% of breast cancers (TNBCs). TNBCs are very aggressive cancers (poor prognosis), known for some years to disproportionally affect young women of African origin – it’s about twice as common in African Americans as in European Americans.

Untitled

The triple negative breast cancer survival rate dependence on race.

African-American women with TNBC have poorer survival rates than women of European descent (Dietze et al., 2015).

Step forward DNA sequencing – again!

What wasn’t known was anything by way of explanation of these epidemiological findings but from sequencing tumour DNA it has emerged that mutations in BRCA1 are present in most (69%) of TNBCs in women of European origin. Inherited mutations in BRCA1 are particularly associated with breast and ovarian cancers, as we explained in a recent item on Angelina Jolie (A Taxing Inheritance). But here’s a very odd thing: African-American women have a low incidence of BRCA1 mutations (less than 20%), despite the fact that they are relatively prone to TNBC.

What’s new?

Well, if BRCA1 isn’t doing the driving there must be other potent drivers for TNBC and the new genetic studies have given us one more piece in the molecular jigsaw of cancer. However, to take up Frances M. Visco’s point in a recent letter to The New York Times and one that I have made forcefully elsewhere (in Not another ‘Great Cancer Breakthrough’!!! and Gentlemen! For goodness’ sake …), this is not another ‘breakthrough’ yet alone a ‘great one.’ It won’t save lives until we identify what the other drivers are and come up with a therapeutic ploy to exploit our knowledge.

Right on cue, step forward Alex Swarbrick, Simon Junankar and colleagues from Sydney’s Garvan Institute of Medical Research who have just found that a protein called ID4 appears to control some TNBCs: it’s present at high levels in about half of all TNBCs. ID4 stands for ‘inhibitor of differentiation 4′ which means that it keeps cells in a state where they can continue to divide – a hallmark of cancer.

So now it’s over to the lads from down under to do the difficult bit and come up with an inhibitor of ID4 – and to show that it works to stop TNBCs in their tracks.

References

Allemani, C. et al., (2015). Global surveillance of cancer survival 1995-2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 385, 977-1010.

Dietze, E. et al., (2015). Triple-negative breast cancer in African-American women: disparities versus biology. Nature Reviews Cancer 15, 248–254.

Junankar, S. et al., (2015). ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. Nature Communications 6, Article number: 6548 doi:10.1038/ncomms7548.

 

Advertisements

Scattering the Bad Seed

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

Metastasis on the move

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

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

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

BOOKMARKING copy

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

So what do we know?

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

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

Tumour cells are not very bright

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

How does it kick off?

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

Making an escape kit

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

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

Spreading variety

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

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

Making friends with the neighbours

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

Not like you see on t.v.

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

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

364

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

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

And the outlook?

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

References

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

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