What’s New in Breast Cancers?

 

One of the best-known things about cancer is that it’s good to catch it early. By that, of course, we don’t mean that you should make an effort to get cancer when you’re young but that, if it does arise it’s a good idea to find out before the initial growth has spread to other places in the body. That’s because surgery and drug treatments are very effective at dealing with ‘primary’ tumours — so much so that over 90% of cancer deaths are caused by cells wandering away from primaries to form secondary growths — a process called metastasis — that are very difficult to treat.

The importance of tumour spreading is shown by the figures for 5-year survival rates. Overall in the USA it’s 90% but this figure falls to below 30% for cancers that have metastasized (e.g., to the lungs, liver or bones). For breast cancer the 5-year survival rate is 99% if it is first detected only in the breast (most cases (62%) are diagnosed at this stage). If it’s spread to blood and lymph vessels in the breast the 5-year survival rate is 85%, dropping to 27% if it’s reached distant parts of the body.

What’s the cause of the problem?

The other thing most people know about cancers is that they’re caused by damage to our genetic material — DNA — that is, by mutations. This raises the obvious notion that secondary tumours might be difficult to deal with because they have accumulated extra mutations compared with those in primaries. And indeed, there have been several studies pointing to just that.

Very recently, however, François Bertucci, Fabrice André and their colleagues in various institutes in France, Switzerland and the USA have mapped in detail the critical alterations in DNA that accumulate as different types of breast cancers develop from early tumours to late, metastatic forms. As is the way these days, their paper contains masses of data but the easiest form of the message comes in the shape of ‘violin plots’. These show the spread of results  — in this case the number of mutations per length of DNA.

Metastatic tumours have a bigger mutational load than early tumours. These plots are for one type of breast tumour (HR+/HER2−) and show results for 381 metastases and 501 early tumours. Red dots = median values: these are the “middle” values rather than an average (or mean) and they show a clear upwards shift in burden as early tumours evolve into metastases. From Bertucci et al., 2019.

The violin plots above are for one subtype of breast cancer (HR+/HER2−). Recall that breast tumours are often defined by which of three types of protein can be detected on the surface of the cells: these are ‘receptors’ that have binding sites for the hormones estrogen and progesterone and for human epidermal growth factor. Hence they are denoted as hormone receptors (HRs) and (human) epidermal growth factor receptor-2 (HER2). Thus tumours may have HRs and HER2 (HR+, HER2+) or various receptors may be undetectable. Triple negative breast cancer (TNBC) is an absence of receptors for both estrogen and progesterone and for HER2.

The plots clearly show an increase in mutation load with progression from early to metastatic tumours (on average from 2.4 to 3.8 mutations per megabase of DNA). Looking at individual genes, nine ‘drivers’ emerged that were more frequently mutated in HR+/HER2− metastatic breast cancers (we described ‘driver’ and ‘passenger’ mutations in Taking Aim at Cancer’s Heart).

So what?

For now these findings give us just a little more insight into what goes on at the molecular level to turn a primary into a metastatic tumour. The fact that some of the acquired driver mutations are associated with poor patient survival offers some guidance as to treatment options.

Don’t get carried away

It’s a familiar story in this field: another small advance in piecing together the jigsaw that is cancer. It doesn’t offer any immediate advance in treatment — mainly because most of the nine ‘driver’ genes identified are tumour suppressors — i.e. they normally act as brakes on cell growth. Mutations knock out that activity and at the moment there is no therapeutic method for reversing such mutations. (The other main class of cancer promoters is ‘oncogenes‘ in which mutations cause hyper-activity).

But such steps are important. The young slave girl in Uncle Tom’s Cabin gave us the phrase “grew like Topsy” — meaning unplanned growth. Cancer growth is indeed unplanned and a bit like Topsy but it’s driven by molecular forces and only through untangling these can we begin to design therapies in a rational way.

Reference

Bertucci, F. et al. (2019). Genomic characterization of metastatic breast cancers. Nature 569, 560–564.

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Keeping Cancer Catatonic

Over a century ago there lived in London an astute physician by the name of Stephen Paget. He was one of those who may or may not be envied in being part of a super-talented family. His Dad, Sir James Paget, was pals with Charles Darwin and, together with Rudolph Virchow, laid the foundations of modern pathology, though today medical students usually encounter his infinitesimal immortality through several diseases that bear his name. These include a rare condition, Paget’s disease of the breast, in which malignant cells form in the skin of the nipple creating an itchy rash, usually treatable by surgery. His Uncle George had been Regius Professor of Physic at Cambridge and he had several brothers, two of whom became bishops. Fortunately Stephen continued the medical thread of the family and Paget’s passion became breast cancer.

A Key Question

Paget had that invaluable scientific gift of being able to pinpoint a key question – in his case ‘What is it that allows tumour cells to spread around the body?’ – and it was such a good question that to this day we don’t have a complete answer. That it happens had been known long before the appearance of Paget Junior. René-Théophile-Hyacinthe Laënnec, French of course, in the early years of the 19th century described how skin cancer could spread to the lungs before he went on to invent the stethoscope in 1816. The mother of this invention was a young lady whom he described as having a ‘great degree of fatness’ that made her heartbeat inaudible by the then conventional method of placing ear to chest. Using a piece of paper rolled into a tube as a bridge, Laënnec was somewhat taken aback that the beat was more distinct than he’d ever heard before. Needless to say, medicine being a somewhat reactionary profession, not all its practitioners had ears tuned to receive this advance with glee but in the end, of course, it caught on and we can therefore award Laënnec first prize in reducing human cumulative embarrassment. It was another French surgeon, Joseph Récamier, who subsequently coined the term metastasis, (to be precise ‘métastase’) to describe the formation of secondary growths derived from a primary tumour.

Early Ideas about Metastasis

The notion that primary tumours could give rise to a diaspora gradually took root but it was not until 1840 that the Munich-born surgeon Karl Thiersch showed that it was actually cells – malignant cells – that wandered off and found new homes. Rudolf Virchow had come up with the idea that spreading was via a ‘juice’ released by primaries that somehow converted normal cells at other sites into tumours. As Virchow was jolly famous, having not only made the study of disease into a science but also discovered leukemia, it took a while for Thiersch to triumph, notwithstanding the evidence of Laënnec and others. Funnily enough, and as quite often happens in scientific arguments, it now looks as though both were right if for ‘juice’ you substitute ‘messengers’ – that is, chemicals dispatched by tumour cells – as we shall see.

Paget’s attention had been drawn to this subject through his observations on breast cancer, and he’d taking as a starting point the most obvious question: ‘How do tumour cells know where to stick?’ Or, as he elegantly phrased it in a landmark paper of 1889: ‘What is it that decides what organs shall suffer in a case of disseminated cancer?’ The simplest answer would be that it just depends on anatomy: when cells leave a tumour and get into the circulation they stick to the first tissue they meet. But in looking at over 700 cases he’d found this just didn’t happen and that secondary growths often appeared in the lungs, kidneys, spleen and bone. Paget acknowledged the uncommonly prescient suggestion a few years earlier by Ernst Fuchs that certain organs may be ‘predisposed’ for secondary cancer and concluded that ‘the distribution of secondary growths was not a matter of chance.’ This led him to a botanical analogy for tumour metastasis: ‘When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.’ From this, then, emerged the ‘seed and soil’ theory of metastasis, its great strength being the image of interplay between tumour cells and normal cells, their actions collectively determining the outcome. Rather charmingly, Paget concluded his paper with: ‘The best work in the pathology of cancer is now done by those who are studying the nature of the seed. They are like scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observation of the properties of the soil may also be useful.’

BOOKMARKING

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., TGFbeta) is secondary tumour growth switched on.

Finding a Landing Strip

For well over a century Paget’s aphorism of  ‘seed and soil’ pretty well summed up our knowledge of metastasis. It’s obvious that before any rational therapy can be designed we need to unravel the molecular detail but we’ve had to wait until the twenty-first century for any further significant insight into the process. As so often in science, the hold-up has been largely due to waiting for the appropriate combination of methods to be developed – in this case fluorescently tagged antibodies to detect specific proteins in cells and tissues and genetically modified mice.

In the forefront of this pursuit has been David Lyden and his colleagues at Weill Cornell Medical College and other centers and their most extraordinary finding is that cells in the primary tumour release proteins into the circulation and these, in effect, tag what will become landing points for wandering cells. Extraordinary because it means that these sites are determined before any tumour cells actually set foot outside the confines of the primary tumour. These are chemical messengers rather equivalent to Virchow’s ‘juice’: they don’t change normal cells into tumour cells but they do direct operations. However, it’s a bit more complicated because, in addition to sending out a target marker, tumours also release proteins that signal to the bone marrow. This is the place where the cells that circulate in our bodies (red cells, white cells, etc.) are made from stem cells. The arrival of signals from the tumour causes some cells to be released into the circulation; these carry two protein markers on their surface: one sticks to the pre-marked landing site, the other to tumour cells once they appear in the circulation. It’s a double-tagging process: the first messenger makes a sticky patch for bone marrow cells that appear courtesy of another messenger, and they become the tumour cell target. It’s molecular Velcro: David Lyden calls it ‘cellular bookmarking.’

Controlling Metastatic Takeoff

Tumour cells that find a new home in this way, after they’ve burrowed out of the circulation, could in principle then take off, growing and expanding as a ‘secondary.’ However, and perhaps surprisingly, generally they do the exact opposite: they go into a state of hibernation, remaining dormant for months or years until some trigger finally sets them off. The same group has now modeled this ‘pre-metastatic niche’ for human breast cancer cells, showing that the switch between dormancy and take-off is controlled by proteins released by nearby blood vessels. The critical protein that locks tumour cells into hibernation appears to be TSP-1 (thrombospondin-1). As long as TSP-1 is made by the blood vessel cells metastatic growth is suppressed. This effect is overridden by stimuli that turn on new vessel growth and in so doing switch secretion from TSP-1 to TGFB (transforming growth factor beta). Now proliferation of the disseminated tumour cells is activated and the micro-metastasis becomes fully malignant. It should be said that this is a model system and may possibly bear little relation to what goes on in real tumours. However, the fact that specific proteins that are, moreover, highly plausible candidates, can control such a switch strongly suggests its relevance and also highlights potential targets for therapeutic manipulation.

Stranger Than Fiction

The system for directing tumour cells to a target seems extraordinarily elaborate. Given that tumour cells cannot evolve in the sense of getting better at being metastatic – they just have to go with what they’ve got – how on earth might it have come about? We don’t know, but the most likely explanation is that they are taking advantage of natural defense mechanisms. Although tumours start from normal cells, the first reaction of the body is to see them as ‘foreign’ – much as it does bugs that get into a cut – and the response is to switch on inflammation and an immune response to eliminate the ‘invader.’

Perhaps what is happening in these mouse models is that the proteins released by the tumour cells are just a by-product of the genetic disruption in cancer cells. Nevertheless, they may signal ‘damage somewhere in the body’. That at least would explain why the bone marrow decides to release cells that are, in effect, a response to the tumour. The second question is trickier: Why should tumours release proteins that mark specific sites? We’ve known since Dr. P’s studies that cells from different tumours do indeed head for different places and it may just be that the messengers arising in the genetic mayhem happen to reflect the tissue of origin. The mouse models, encouragingly, show that the target changes with tumour type (e.g., swap from breast to skin and the cells go somewhere else). In other words, tumours send out their own protein messengers that set up sticky landing strips in different places around the circulation.

As for take-off, it may be that newly arrived tumour cells simply adapt to the style of their neighborhood. By and large, the blood vessels are pretty static structures: they don’t go in for cell proliferation unless told to do so by specific signals, as happens when you get injured and need to repair the damage. TSP-1 appears to be a ‘quiescence’ signal, telling cells to sit tight. The switch to proliferation comes when that signal is overcome by TGFB, activating both blood vessels and tumour. All of which would delight Paget: not only is our expanding picture consistent with ‘seed and soil’ but the control by local signals over what happens next makes his rider that ‘observation of the properties of the soil may also be useful’ spot on.

References

Kaplan, R.N., Riba, R.D., Zacharoulis, S., Bramley, A.H., Vincent, L., Costa, C., MacDonald, D.D., Jin, D.K., Shido, K., Kerns, S.A., Zhu, Z., Hicklin, D., Wu, Y., Port, J.L., Altork, N., Port, E.R., Ruggero, D., Shmelkov, S.V., Jensen, K.K., Rafii, S. and Lyden, D. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820-827.

http://www.ncbi.nlm.nih.gov/pubmed/16341007

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

http://www.readcube.com/articles/10.1038/ncb2767