How does obesity increase cancer risk?

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Obesity is associated with an increased risk of many types of cancer, including esophageal, gastric, colon and rectum, liver, gallbladder, pancreas, breast, uterine, ovarian, kidney, meningioma, thyroid, and multiple myeloma. Further, for many of these cancers, a progressively higher body mass index (BMI) is associated with progressively greater risk.

So how does excess fat tissue increase cancer risk?

A recent review article on adipose (fat) tissue and cancer summarizes current knowledge on this topic.

Ways in which excess fat tissue drives cancer include:

Metabolic syndrome. Fat in and around the abdomen is called visceral fat. This type of fat makes hormones and inflammatory chemicals that lead to insulin resistance, which can lead to metabolic syndrome, including type 2 diabetes. Hormones produced by visceral fat such as leptin have important effects on cancer, and are prognostic factors for several types of cancer, including endometrial, breast, kidney, and liver . Dysfunction and insulin resistance of visceral fat leads to an increase in circulating free fatty acids, pushing fat storage to other organs that were not meant to store fat, such as the liver and pancreas (this is called ectopic fat). With a longer duration of obesity, visceral fat develops progressive fibrosis (scarring) and immune cell infiltration, which worsens its impact on the body’s metabolic health. Low levels of the hormone adiponectin, as is seen in obesity, is also associated with the risk of developing and/or the prognosis for several types of cancer, including breast cancer, melanoma, endometrial (uterine), kidney, and liver cancer.

Tumors often develop embedded in, or near, fat tissue (eg breast, pancreatic, kidney, melanoma, prostate, multiple myeloma). Fat tissue that is adjacent to tumor tissue ‘talks’ to the tumor via inflammatory chemicals and hormones, directly affecting tumor development, growth, and progression (called ‘paracrine effects’). The fat tissue also responds to hormones produced by the tumor, allowing the tumor to settle in, draw energy from the fat tissue for growth, and even develop blood supply networks that feed the tumor.

Changes in gut bacteria (called the microbiome) and epigenetic changes seen in obesity also play a role in promoting cancer.

There are also some unique features linking obesity with certain specific types of cancer.

Many studies have demostrated a role of breast fat in driving growth and progression of estrogen receptor positive breast cancer via increased production of estrogen by the excess breast fat.

Endometrial cancer is associated with obesity and polycystic ovary syndrome (PCOS). Women with PCOS often have infrequent periods, meaning that the lining of the uterus that should be shed during a period (endometrium) builds up, which can lead to transformation into cancer cells.

Ectopic fat buildup in certain organs such as the liver and pancreas may drive cancers in these organs, by releasing inflammatory factors and hormones that may promote cancer development and progression.

The relationship between obesity and prostate cancer is not fully clear. Many men with obesity have low testosterone, and since prostate cancer is responsive to testosterone, this could theoretically be protective. However, the literature as a whole suggests a small increased risk of prostate cancer related to obesity. Importantly, several studies suggest a relationship between obesity and aggressiveness of prostate cancer, with a higher risk of both recurrence and prostate cancer-specific death. The prostate gland is embedded in fat, and the thickness and size of this fat depot has been associated with a worse prognosis.

So: does weight loss reduce the risk of cancer?

As blogged previously, it has been difficult to prove whether weight loss reduces cancer risk. Some observational studies have suggested that a smaller amount of weight loss (eg 5-10%) may reduce cancer risk. With bariatric surgery, which typically results in a much larger magnitude of weight loss (25-30%), the available clinical trial data suggest that there is a lower risk of developing obesity-associated cancer. Now that we have new and emerging weight management medications that can result in a similar amount of weight loss as bariatric surgery, we need to study whether medication-facilitated weight loss may also reduce obesity-related cancer risk.

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