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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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.