Fatbergs Block Cancer Defences

 

Most people are aware that being seriously overweight is a health hazard — and it’s a big one because nearly 2 billion adults are overweight or obese. Obese people are 80 times more likely to get type 2 diabetes than those of normal weight, they’re more likely to suffer from heart and blood vessel disease and they have an increased risk of cancer. In fact about half of some types of cancer are caused by obesity and in the UK more than 1 in 20 cancers are due to excess weight — making it the second largest preventable cause of cancer (smoking, of course, being the first).  Indeed, new figures from Cancer Research UK published a few days after I wrote this piece tell us that now obese people outnumber smokers two to one and being overweight causes more cases of certain cancers than smoking.

As you know

Obesity is associated with abnormal levels of hormones involved in growth (e.g. insulin, oestrogens and leptin). It’s generally thought that their raised levels also favour cell proliferation and tumour growth. Nevertheless, despite the figures showing a clear link, it’s been a slow business to unearth the molecular links between obesity and cancer. And that knowledge is, of course, essential if we’re to come up with ways of interfering with the process.

In Obesity and Cancer we noted that two things happen as obesity develops: the number of fat (adipose) cells goes up but they also grow bigger (i.e. the fat cells themselves are fatter).

This causes a knock-on effect that is even more serious: the fat cells attract other cells from the circulation and this cellular cooperative releases signalling proteins that can drive tumours.

In obesity abnormal signals from fatty tissue can combine with others arising from perturbed metabolism to help cancers develop.

With that background we described in Isn’t Science Wonderful? Obesity Talks to Cancer the discovery that cells recruited into the tumour neighbourhood can talk directly to the tumour cells. They do this by releasing the messenger leptin — a hormone made by adipose cells that stops us feeling hungry.

The cellular ‘groupies’ that make leptin are fibroblasts – part of the supportive framework of cells and tissues, so they’re ‘cancer-associated fibroblasts’— rather than fat cells, but that’s slightly by the by.

Now comes another piece of the jigsaw, courtesy of Xavier Michelet, Lydia Dyck and colleagues from institutes in Boston, Kentucky and Ireland, who have shown that one upshot of obesity can damage our anti-cancer defences. It does this by taking aim at natural killer cells (NK cells) — a sub-group of white blood cells (lymphocytes) that are a key bit of our immune system when it comes to destroying tumour cells. NK cells attack tumour cells directly, making holes in their outer membranes and essentially blowing them up.

Obesity paralyses immune cells. The two images are of immune cells from (left) lean and (right) obese individuals. The cells were stained with a fluorescent indicator that detects fat molecules. White bar = 10 microns (i.e. one 10 thousandth of a metre). From Michelet et al. 2018.

Michelet and colleagues showed that circulating free fatty acids (FFA) are taken up by NK cells. As the levels of FFAs are raised in obese individuals, their NK cells accumulate FFAs. The photo above shows how abnormal these fat-loaded cells look and it’s no surprise that their metabolism gets upset. Critically for their anti-tumour activity, this disruption cuts production of the proteins that target tumour cells (perforin and granzymes).

So at last we have a clear molecular link between obesity and cancer: the raised levels of FFAs push a metabolic switch in NK cells that blocks their ability to kill tumours cells — so a major repressor of tumour growth is overcome.

Reference

Michelet, X. et al. (2018). Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology 19,1330–1340.

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