Why Does Cancer Risk Result from Excess Fat Tissue?

Here I'll point out a recent popular science article on the mechanisms underlying the correlation between cancer and obesity. It is well known and well proven by the scientific community that being overweight is bad for you, even if large sections of the public appear to be solidly in a state of denial on this topic. If you choose to carry excess visceral fat tissue for any great length of time as an adult, even decades later, even having lost that weight, the demographic data strongly suggests that you have a significantly increased risk of suffering all of the common age-related conditions: cancer, heart disease, dementia, and so forth. If you maintain that fat - or keep adding to it over the years, as an increasingly large fraction of the population does - then your odds become even worse. The more fat tissue you have, and the longer you have it for, the shorter your life expectancy, the more you will spend on medical expenses, and the less healthy you will be over the long term.

When trying to explain why this is the case, what it is under the hood that connects fat tissue to ill health, the first candidate mechanism on the list is chronic inflammation. In fact, whether or not you put on weight with age, the growing dysfunction of your immune system will cause rising levels of chronic inflammation, and this inflammation contributes to the pathology of near all of the common and fatal age-related conditions. Fat tissue makes this progression faster and a lot worse, however. Visceral fat is metabolically active; it does a lot to shift the alteration of human biochemistry, and the more of it there is the more it distorts the normal operation of metabolism. The inflammation is most likely caused by some combination of signals from visceral fat tissue that aggravates the immune system, producing results such as a feedback loop of abnormal behavior in macrophage cells.

Nothing in biology has only a single cause, however. Everything is complicated, everything interacts with other mechanisms. The relationship between fat tissue and age-related disease is going to be a story that spreads far beyond inflammation, for all that inflammation is the obvious starting point given what is known of its importance in aging. Take a look at this article, for example, which focuses only on the interactions of cancer and fat tissue:

Breaking the Cancer-Obesity Link

The most recent data from the National Center for Health Statistics indicate that 69 percent of US adults are overweight and half of those are obese. Worldwide, an estimated 2.2 billion adults are overweight or obese, and many of these individuals exhibit the hallmarks of metabolic syndrome: elevated blood pressure and high levels of blood sugar and cholesterol. Increased circulating levels of insulin, inflammatory cytokines, and other factors are also common in obese individuals. And while these metabolic and immune changes are problems in and of themselves, they are not the only health issues faced by the obese population. Through these and other possible mediators, obesity increases the risk and/or worsens the outcome of several chronic diseases, including many types of cancer. This year, obesity overtook smoking as the top preventable cause of cancer death in the U.S., with some 20 percent of the 600,000 cancer deaths per year attributed to obesity.

A major challenge in understanding the complex relationship between obesity and cancer has been distinguishing which host factors are causally linked and which are simply bystanders. Obesity can induce a complex state of systemic metabolic dysregulation characterized by insulin resistance and high levels of circulating insulin and glucose. Over the last two decades, however, researchers have used genetic or pharmacologic approaches to make progress in deciphering which of the many changes mediates the obesity-cancer link. Intercellular signaling is undoubtedly one contributing factor. Proteins, lipid intermediates, and other molecules secreted or shed from cells - collectively referred to as the secretome - carry messages between distant organ systems and tumor cells, as well as among tumor and host cells in their microenvironment. These signaling pathways involve an increasingly large roster of obesity-related hormones, growth factors, nutrient metabolites, chemokines, and cytokines that promote tumor development and/or progression. For example, insulin resistance in obese individuals drives insulin production in the pancreas and results in excess insulin in circulation. High levels of insulin can promote cancer growth through interaction with tumor cells' insulin receptors and/or IGF-1 receptors. Expression of the IGF-1 receptor is also necessary for the transformation of normal epithelial cells into cancer cells by numerous oncogenes, suggesting that greater IGF-1 signaling can also enhance the early stages of cancer development. In addition to the secretome, the tumor microenvironment encompasses extracellular matrix components and multiple cell types, including adipocytes and macrophages, which in obese people are highly active and capable of secreting a large number of cancer-promoting hormones and cytokines.

Another factor that appears to be involved in the obesity-inflammation connection, but has not yet been strongly linked to cancer risk and progression, is the gut microbiome. Obesity is associated with an overall reduction in gut bacterial diversity, and decreased bacterial richness has been linked to elevated systemic inflammation. These studies suggest that obesity-related perturbations of the gut microbiome and barrier function associated with a high-calorie diet can induce chronic systemic and adipose tissue inflammation, which is known to play a role in the progression of several cancer types.

In addition to putting people at an increased risk for developing cancer, obesity also worsens a cancer patient's prognosis. Research from our group and others has shown that a variety of cancers grow at faster rates in obese patients than in lean individuals. Furthermore, obesity appears to increase the chances that a patient's cancer will metastasize. A variety of factors may underlie the obesity-metastasis link, including circulating factors such as leptin, adiponectin, and IGF-1; adipose tissue remodeling, including alterations in adipose-derived stem cells; and other changes to the tumor microenvironment.


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