How Does Obesity Cause Cancer? Three Leading Theories

scale, weight
Credit Flickr/Paola Kizette Cimenti. Posted under this Creative Commons license.

This blog post was originally published on the Cancer Research UK science blog. It’s reposted here with minor edits.

‘Love handles’, ‘muffin top’, ‘beer belly’, ‘extra padding’, ‘cuddly bits’, ‘winter insulation’… We all have names for the squishy bits we keep meaning to lose – but apart from not fitting into our favorite jeans, carrying too much weight isn’t actually doing any harm, is it?

Unfortunately, it is. But despite efforts to raise the profile of the link, public awareness remains stubbornly low. This is an urgent problem: the world is slowly drifting into an obesity crisis, with the condition already linked to nearly 500,000 cancer cases worldwide every year.

According to recent reports, public health experts predict that – shockingly – in the US obesity will soon overtake tobacco as the leading preventable cause of cancer.

So it’s clear that those spare pounds aren’t a mere overflow parking lot for excess donuts.

But that raises a crucial question: how exactly does fat increase our risk of cancer?

While there are several plausible explanations, it’s an answer that researchers are still working hard to figure out. But first… just what is fat?

Fat isn’t just padding: it’s like another organ

Fat (also known as adipose tissue) has two main roles in the body.

Primarily it exists to store calories in the form of chemicals called lipids, which – when food was scarce would serve as a back-up energy store to keep us going. But nowadays many people consume more calories than they use up, leading to more of us becoming overweight or obese.

But the fat in your body also has a secondary function – it’s essentially a huge gland, sending out a constant stream of biological information and instructions that affect the rest of your body. This helps control processes like growth, metabolism and reproductive cycles.

But because of their ability to turn biological processes on and off, the signals produced by fat have a darker side when it comes to cancer.

This is especially true when people become overweight or obese – the point at which excess fat has a negative impact on health. Here are the three leading theories about how excess fat might lead to cancer, and the scientific evidence behind each one.

Infographic credit Cancer Research UK
Infographic credit Cancer Research UK

1. The estrogen connection

One of the strongest links between obesity and cancer is an increased risk of breast and womb cancers in women who are overweight or obese after the menopause, and this relates to higher estrogen levels.

In pre-menopausal women, the ovaries are the main estrogen-producing cells. But fat cells can make estrogen too and, after the menopause, when the ovaries stop working, fat becomes the chief source of the hormone. And there is solid evidence showing that being obese leads to higher estrogen levels in women after the menopause.

Professor Martin Wiseman, a leading expert on diet, weight and cancer from the World Cancer Research Fund, is in no doubt that estrogen made by fat cells is a leading culprit in postmenopausal breast and womb cancer.

“The evidence that estrogen plays a central role in some cancers is black and white. Estrogen makes certain cells – like breast and womb cells – divide, so too much estrogen can encourage cells to keep dividing when they shouldn’t be. And uncontrolled cell division is fundamentally what cancer is.

“Large studies of women have shown a direct relationship between obesity, high estrogen levels and breast and womb cancers”, he explains, “and understanding this relationship has been critical in developing effective treatments – like tamoxifen and aromatase inhibitors – that work by cutting off estrogen.

“Furthermore, if women at high risk of breast cancer are given estrogen-blocking treatments, fewer go on to develop the disease. Cutting off estrogen can stop breast cancer developing.”

While the link to women’s cancers is stronger, there’s also data suggesting that obesity-related changes in sex hormones can play a role in men’s cancers too. There’s evidence that, while rare, breast cancer in men is linked to increased estrogen caused by excess body fat. Obesity is also linked to higher rates of aggressive prostate cancer, but it’s unclear if changes in estrogen from fat cells play a role, or whether it could be down to changes in testosterone, the male sex hormone.

2. Metabolic chaos

The chemical processes going on constantly throughout the body – collectively known as metabolism – are complicated and tightly controlled, relying on a finely tuned web of information flowing between cells and organs.

But the chemical signals produced by fat cells means that obesity can cause a major upset to this balance, and this is thought to be another way it makes cancer more likely.

One key hormone that acts as a master-controller of metabolism is insulin. It’s made by the pancreas and orchestrates how cells take up and process glucose from the blood.

But insulin’s instructions can be overridden by chemicals in your blood known as free fatty acids – the levels of which can be affected by eating a fatty meal, for example. This flips a switch in your liver and muscles, telling them to use this fat as fuel instead of glucose.

But it’s not just eating fatty food that increases free fatty acid levels in blood. Body fat, especially around the abdomen, can also release them – it’s the body’s way of using up fat stores. Excess body fat can lead to rising levels of free fatty acids, leaving cells increasingly resistant to the effects of insulin and unable to take up glucose properly.

“This can cause all kinds of problems,” Wiseman tells us. “Cells become resistant to insulin, so the pancreas makes more to try and compensate and bring blood glucose levels back down.”

And these long-term raised insulin levels could be another way being obese raises the risk of cancer, he says.

“Higher amounts of insulin have a knock-on effect of re-programming the levels of growth factors available to cells, and both insulin and these growth factors can become a danger when it comes to cancer. Growth factors are a green light signal for cells to divide.”

There’s also substantial laboratory evidence of a link: lots of data showing that as cancer cells react to both insulin and insulin-related growth factors, they become harder to kill, and divide more quickly.

“Large studies of peoples’ blood chemistry have also shown links between high glucose (even at levels below those needed for a diagnosis of diabetes) and the risk of several types of cancer,” Wiseman tells us.

Taken together, the evidence that disturbances in metabolism lead to cancers is compelling.

The big question is the degree to which it plays a role in the increased rates of cancer in obese people – and studies are ongoing to find this out.

3. Inflammation

As people become obese, and more fat cells build up in their tissues, specialized immune cells (called macrophages) are called to the scene, possibly to clear up dead and dying fat cells.

But as macrophages carry out their clean up job, they also release a potent cocktail of chemicals called cytokines that summon other cells to help them out. The number of macrophages in obese fatty tissue can be substantial – they can account for as many as four in 10 cells.

This ultimately creates a condition called chronic inflammation – and this is another way that obesity is thought to fuel the development of cancer. And it’s been shown that obese people tend to have higher levels of inflammatory cytokines in their blood.

Inflammation can be a double-edged sword – while it’s an essential part of our immune defenses, it can also aid and abet the growth and spread of cancer.

The evidence that inflammation is linked to cancer is damning. Many chronic inflammatory diseases (such as pancreatitis and Crohn’s disease) can increase a person’s risk of cancer. And cancers caused by infections are also characterized by chronic inflammation.

Wiseman explains “the result of inflammation is a cocktail of signals that tell cells to divide, because after injury you need new cells for healing to occur.

“But the signals encouraging cell growth for healing can also support cancer cells dividing. In fact if we look at the genes that are turned on and off in inflamed tissue, it’s very similar to genetic changes we see in cancer cells.

“piriThere’s strong evidence that aspirin, a drug that reduces inflammation, prevents bowel cancer, or other anti-inflammatory drugs may also be beneficial when it comes to treating, and possibly preventing, other types of cancer.”

This doesn’t add up to concrete evidence of inflammation playing a role in cancer, but it certainly points a strong finger of accusation in its direction.

The long and short of it

There’s not a shadow of doubt that obesity is linked to cancer, but unraveling the biological reasons why is proving complicated.

Being obese affects lots of different aspects of our physiology – hormones, growth signals, and inflammation. It also affects different people in different ways; for example, not everyone who is obese will have abnormal metabolism or chronic inflammation.

To make matters more complicated still, estrogen, insulin, and inflammation are a convoluted tapestry of interwoven threads. None of them in isolation directly causes cancer, but in obesity they knit together to form a lethal fabric – dampening the delicate systems that balance our bodies with disastrous consequences.

And while it’s not simple to understand how the threads weave into the overall picture, researchers know that there’s potentially an opportunity to treat, or even prevent, cancer by developing drugs that override signals made by fat cells. For example, both metformin (a diabetes drug that affects insulin levels) and aspirin (which dampens down inflammation) are under investigation as possible anti-cancer drugs.