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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Isn’t Science Wonderful? Obesity Talks to Cancer

A couple of week’s ago we looked at how being obese can give cancer a helping hand. I thought this would be useful as most people know there is a link but perhaps not much more than that. The message had two simple parts: (1) When we make extra fat cells they change the metabolism of our bodies through chemical signals that wander around and, in passing, can also drive cancer growth, and (2) Some of the extra fat cells congregate around tumours and give them direct positive vibes (i.e. other, local chemical signals).

But you may have spotted that I didn’t actually say what these ‘signals’ are – for the very good reason that we know rather little about them. Step forward, right on cue, Ines Barone, Suzanne Fuqua and friends from the University of Calabria and Baylor College of Medicine, Houston with a wonderful paper that’s just been published. Wonderful because it’s got so much data I’m green with envy but also because, like most excellent science papers, the key message is simple: normal cells that have moved into the neighbourhood can indeed talk directly to tumour cells. And the messenger is … leptin!

That’s astonishing. Even those with only a smattering of knowledge about how we work will know that leptin plays a key role in regulating energy balance. It’s a protein – a hormone – that circulates in our blood at levels roughly proportional to body fat. Its job is to signal the ‘full’ state, i.e. to reduce appetite. Somewhat perversely, obesity usually causes abnormally high leptin levels but it doesn’t work very well because the body has become resistant to its signal – much as happens with insulin in type 2 diabetes.

The new results show that leptin, released from nearby cells, can bind to cancer cells and make them do two things: (1) Release a chemical that tells the adjacent cells to send out even more leptin, and (2) Make proteins that help the tumour cells grow and invade.

There are a few wrinkles to these results. The study was on breast cancer cells with a particular mutation (in a receptor for the hormone estrogen) and the ‘groupies’ providing the leptin turned out not to be fat cells but fibroblasts – part of the supportive framework of cells and tissues – so they’re ‘cancer-associated fibroblasts’ (CAFs). And when the CAFs release leptin it floods out and the tumour cells embrace it and make yet more receptors for leptin to bind to on their surface.

But these details matter less than the key point: for at least some types of cancer cell a hormone often made in excessive amounts in obesity can signal directly to tumour cells, telling them to grow and spread. This doesn’t mean that all breast tumours, yet alone all cancers, respond to leptin. What it does show is that a key factor in obesity can talk directly to some types of tumour cell. It’s another example of the painstaking way in which science usually proceeds and, assuming the results are reproducible, we have one more little bit of the jig-saw.

Reference

Barone, I., Catalano, S., Gelsomino, L. et al. (2012). Leptin Mediates Tumor−Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells. Cancer Research 72, 1416-1427.