• Phoebus Tian

There is growing scientific evidence that obesity is closely linked to cancer

We tend to eat more and move less, making overweight and obesity a worldwide health problem. Not only is obesity-prone to chronic diseases such as high blood pressure and diabetes, but there is also a growing body of scientific evidence linking obesity to cancer. Obesity is now known to increase the risk of more than a dozen cancers, including colorectal, breast, liver and pancreatic cancers, and is associated with poor prognosis and reduced survival rates.

Recently, in the leading academic journal Cell, scientists from Harvard Medical School have shown through animal studies that obesity caused by a high-fat diet feeds cancer cells and "starves" the immune cells inside the tumour, thus weakening the immune cells' ability to fight cancer and accelerating tumour growth.

The researchers say this finding provides the basis for a better understanding of how obesity affects cancer and the impact of patient metabolism on treatment outcomes.

In this study, the scientists used mouse models of various cancers, including colorectal, breast, melanoma and lung cancers, to study the impact of obesity.

To do this, the researchers gave the mice a high-fat diet with 60 per cent fat energy supply. Compared to a control group on a normal diet, the high-fat diet caused the mice to gain weight quickly, become fat and also develop metabolic problems such as hyperlipidemia. The researchers then implanted these mice with cancer cells. They found that the tumours tended to grow faster in the obese mice on the high-fat diet compared to the normal diet group.

The researchers analysed in detail how the various types of cells and molecules within and around the tumours of the mice, i.e. the tumour microenvironment, differed between the two dietary models. Using different methods such as single-cell gene expression analysis, large-scale protein surveys and high-resolution imaging, the team found many changes in the metabolic pathways of cancer cells and immune cells.

Metabolic mapping showed that cancer cells are very good at regulating their metabolism in response to changes in fat availability. As whole-body fat increases, cancer cells increase their uptake and utilisation of fatty acid molecules. Specifically, cancer cells in obese mice reduce the expression of a protein called PHD3, which in normal cells would prevent excessive fat metabolism. Further experiments showed that regulating PHD3 in tumour cells could alter their ability to take up fatty acids.

Fatty acids are essential cellular fuels, and because cancer cells consume large amounts of certain key free fatty acids, CD8-positive T cells in the tumour microenvironment are deprived of essential cellular fuels and have to 'starve'!

CD8-positive T cells are an important class of immune cells that can target and kill cancer cells and are the primary weapon in many cancer immunotherapies. However, experiments have shown that obesity caused by a high-fat diet reduces the number of CD8-positive T cells in the tumour microenvironment. Not only were there fewer of them, but they also divided at a slower rate and had reduced activity levels. In other words, the ability of these immune cells to fight cancer was weakened.

"The paradox of depleting fatty acids in this study was one of the most surprising findings to us." Alison E. Ringel, PhD, author of the study, said, "It's an exciting finding that obesity and changes in whole-body metabolism can alter the way tumour cells utilise fuel."

Based on this discovery, the scientists also proposed new strategies to improve immunotherapy in this study, targeting the metabolic needs of immune cells. They experimented with genetic means to increase the expression of PHD3 in cancer cells in mice, and the experimental results showed that it was possible to increase CD8-positive T-cell activity, largely reversing the negative effects of a high-fat diet on tumour immune cells and slowing tumour growth in obese mice.

The team also analysed the human cancer genome database and found that obese patients with a BMI above 30 had significantly lower expression of PHD3, and their tumours were more likely to be 'cold' tumours with fewer immune cells. These results also confirm that obesity reduces the ability of immune cells to fight cancer in many cancers and that PHD3 may provide a potential therapeutic target.

Ringel AE, Drijvers JM, Baker GJ, Catozzi A, García-Cañaveras JC, Gassaway BM, Miller BC, Juneja VR, Nguyen TH, Joshi S, Yao CH, Yoon H, Sage PT, LaFleur MW, Trombley JD, Jacobson CA, Maliga Z, Gygi SP, Sorger PK, Rabinowitz JD, Sharpe AH, Haigis MC. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell. 2020 Dec 7:S0092-8674(20)31526-9. doi: 10.1016/j.cell.2020.11.009. Epub ahead of print. PMID: 33301708.

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