How are Obesity and Weight Loss related to your risk of cancer?

PET Scans

Illustration of the small intestine in the intestinal system

Cancer is the name for a group of diseases in which cells in a specific part of the body divide and grow abnormally to form clusters known as tumors. All body tissues are formed from cells whose behavior is governed by genes. Under normal circumstances, cells reproduce and die at an equal rate, but if the gene responsible for controlling this aspect of cell behavior changes or mutates then the cell can begin to replicate uncontrollably. Gene mutations are classified as inherited or acquired: Inherited or germline gene mutations are hereditary and increase an individual’s susceptibility to a certain form of cancer. They are much less common than acquired or somatic mutations, which can occur by chance or be triggered by some external influence such as exposure to a particular virus or carcinogenic substance. There are over 200 forms of the disease, which is extremely common within the general population, with more than one in three people developing some form of cancer during their lifetime.

Obesity and its Relationship with Cancer Pathogenesis

Whilst the link between cancer and obesity has been the focus of significant research for some time, no single causal pathway has been identified and at present it is not clear whether obesity is responsible for causing the gene mutations that can initiate cancer, or if it somehow promotes cancer progression such that the disease is detected at an earlier age than would otherwise be typical. There is some evidence to support both mechanisms.

Fat, or adipose tissue is metabolically active, impacting upon levels of various hormones within the body including insulin, leptin, adiponectin and estrogen. A central or abdominal pattern of fat distribution is known to be more metabolically disruptive than general obesity. Leptin, which is present at higher levels in obese individuals, is associated with increased cell proliferation, whilst adiponectin, which is less plentiful in obese individuals, is associated with inhibition of cell growth.

In premenopausal women, the majority of estrogen is produced by the ovaries. When ovarian estrogen production ceases following the menopause, adipose tissue becomes the main source of estrogen in obese women, who may therefore have significantly higher levels of the hormone within their blood stream than non-obese women. These elevated levels of estrogen have been implicated in the pathogenesis of several cancers including endometrial and breast cancer.

Obesity can result in a chronic low-grade inflammatory state as metabolic tissues within the liver, muscles, brain, pancreas and other parts of the body react to an overabundant supply of nutrients and energy. Subacute inflammation is linked to increased risk of cancer, and is also thought to play a part in the pathogenesis of other obesity-related conditions, including insulin resistance. Physical inactivity, which is common amongst obese individuals, is positively associated with increased risk of developing several forms of cancer, whilst regular exercise is known to have an anti-inflammatory effect.

Insulin resistance, where the body produces insulin but does not respond to it appropriately, may promote the development of certain types of tumor and is also a precursor to type 2 diabetes, which is itself a risk factor for developing some forms of cancer. Insulin resistance leads to elevated levels of insulin within the blood stream, and high insulin levels are commonly observed in many forms of cancer. Dietary fat is also known to activate inflammatory pathways within the body, and there is some evidence to suggest that a high fat diet may promote the progression of cancer independently of diabetes or obesity.

Oxidative stress is a term used to refer to pathologic changes within the body initiated by a chemically reactive class of molecules known as the reactive oxygen species (ROS), which includes free radicals and peroxides. The majority of ROS are generated as byproducts of essential metabolic processes, but they can also be introduced through exposure to external sources such as cigarette smoke, environmental pollutants, ionizing radiation and through infection by fungal, viral or bacterial agents. Level of oxidative stress is dependent upon the rate at which damage occurs relative to the rate at which it can be overcome by the body’s antioxidant cellular defense mechanisms. An increase in oxidative stress can be initiated by increased production of ROS, exposure to external ROS sources and/or a failure in the body’s ROS defense system.  A role has been proposed for elevated levels of oxidative stress in the pathogenesis of multiple conditions including cancer, cardiovascular disease and various neurodegenerative diseases, and several studies have found a positive relationship between BMI and elevated levels of oxidative stress. Inflammation is known to result in increased ROS production so it is possible that oxidative stress provides a link between obesity-related chronic inflammation and cancer pathogenesis.

Cancers Linked to Obesity

Obesity is a leading modifiable risk factor for cancer in the US, second only to tobacco usage. It is associated with particular risk for developing cancer of the esophagus, pancreas, bowel, thyroid, gallbladder, endometrium and kidney, as well as postmenopausal breast cancer. More limited evidence also exists to suggest a link between obesity and increased susceptibility to other forms of the disease including multiple myeloma, premenopausal breast cancer and non-Hodgkin’s lymphoma.

Esophageal Cancer

The esophagus is a tube that connects the stomach to the mouth. Two different forms of esophageal cancer can occur, depending on the type of cells involved. Squamous cell esophageal carcinoma is strongly associated with smoking and alcohol consumption, but not linked to obesity. Adenocarcinoma is far more common in obese than non-obese individuals and is linked to the presence of gastroesophageal reflux disease (GERD) and, in particular, a condition known as Barrett’s esophagus, for which obesity is a known risk factor.

Thyroid Cancer

The butterfly-shaped thyroid gland, located in the front portion of the neck, produces several hormones including triiodothyronine (T3) and thyroxine (T4) and is responsible for regulating various physiological processes including metabolic rate, protein production and hormonal sensitivity. Several different forms of thyroid cancer have been identified, of which the papillary and follicular variants are the most common.  The primary symptom of thyroid cancer is the presence of a painless lump or nodule in the neck.

Obese individuals tend to present with more aggressive forms of papillary thyroid cancer than their non-obese counterparts and research also indicates that thyroid cancer is often diagnosed at a more advanced stage in obese individuals, with a trend towards larger tumors with increasing BMI. The cause of thyroid cancer within the general population is largely unclear, but it is suspected that some aspect of obesity plays a part in physiological development of the more aggressive form of the disease, whilst late diagnosis is attributed to the fact that larger neck size makes it more difficult to feel lumps and nodules during physical examination. Most thyroid cancers are treatable, but late detection is associated with increased mortality, so some specialists advocate ultrasonographic screening of obese patients over 45 years of age.

Gallbladder Cancer

The gallbladder is a small pouch-like organ located just below the liver. It stores and concentrates a digestive fluid known as bile, produced by the liver, releasing it into the duodenum when fatty foods are eaten in order to aid fat digestion. Adenocarcinoma is the most common form of gallbladder cancer, affecting the cells that line the gallbladder. It displays a strong female preponderance and is uncommon in those under 50 years old, most frequently occurring in individuals over the age of 70. There are several risk factors for the disease, including a history of other gallbladder conditions such as gallstones, bile duct abnormalities, porcelain gallbladder and gallbladder polyps, as well as smoking, family history and obesity.

A positive relationship exists between BMI and susceptibility to gallbladder cancer, with some studies suggesting a stronger association between obesity and gallbladder cancer risk in women than men. The mechanisms underlying these associations are unclear but the disruptive effect of excess body fat upon hormones including estrogen and insulin may be implicated. Additionally, obese individuals are at increased risk of developing gallstones, which itself increases the risk of developing gallbladder cancer.

Kidney Cancer

The kidneys are located below the ribcage, towards the back of the body. Roughly fist-sized and shaped like kidney-beans, their purpose is to filter waste products from the blood stream to be excreted as urine. Obesity is associated with an increased risk of developing renal cell carcinoma – the most common form of kidney cancer - in both men and women. Whilst hypertension is another known risk factor for the disease, and is also common in obese individuals, the link between renal cell carcinoma and BMI exists independently of hypertension.

Endometrial Cancer

Endometrial cancer is a type of cancer that initially develops within the lining of the womb or uterus, of which the most common form is adenocarcinoma. Obesity is very strongly linked to increased risk of developing endometrial cancer, with positive relationships existing between both BMI and weight-to-hip-ratio (WHR) and increased susceptibility to the disease. Endometrial cancer is most common in women between the ages of 60 and 80, and some studies suggest obesity may be a contributory factor in up to 50% of incident cases. No link has been identified between obesity and endometrial cancer grade or progression, but current research suggests that the hormonal changes observed in obese women may be directly linked to promotion of endometrial cancer cell growth. Type 2 diabetes is also a known risk factor for developing endometrial cancer.

Postmenopausal Breast Cancer

The link between obesity and postmenopausal breast cancer is well established, with research indicating a potential increase in risk of up to 30% for obese versus non-overweight women. Obesity at time of diagnosis is also associated with poorer prognosis. The elevated levels of estrogen observed in obese postmenopausal women are thought to play a significant part in pathogenesis of the disease. Distribution of body fat may also be a factor, with a high-waist-to-hip ratio associated with additional risk.

There is some evidence to suggest that the time of life in which a woman gains weight may contribute towards susceptibility to the disease: Several studies have reported that women whose BMI increases between the age of around 20 years and onset of the menopause at between 50 and 60 years of age are at greater risk of developing postmenopausal breast cancer than women whose BMI remains stable during the same period of time, irrespective of initial BMI at age 20.

Bowel Cancer

Bowel cancer is a general term for various cancers that arise within the large bowel. Depending on where the cancer originates, it may be classified as colon cancer or rectal cancer. Colon cancer is significantly more common in obese individuals with men in particular showing increased susceptibility to the disease in relation to elevated BMI. The risk of developing rectal cancer also increases in relation to BMI, but to a lesser extent than colon cancer. When WHR rather than BMI is used as a measure of body fat, women also display increased susceptibility to bowel cancer, suggesting that the presence of central obesity may contribute towards development of the condition in women. Physical inactivity and a diet high in red meat and saturated fat and low in fiber are also associated with increased risk of bowel cancer.

Pancreatic Cancer

The pancreas is part of the digestive system, located within the upper part of the abdominal cavity, behind the stomach. It produces pancreatic juice, a fluid containing enzymes that aid in the digestion of carbohydrates fats and proteins within the small intestine. It also functions as an endocrine gland, secreting various hormones including insulin.

Obesity and diabetes are associated with increased risk of developing pancreatic cancer. A positive relationship exists between BMI and susceptibility to the disease, but since diabetes risk is also positively associated with elevated BMI the causal relationship between obesity, diabetes and pancreatic cancer remains unclear. There is some evidence to suggest that diet may also be a factor, with consumption of meats cooked at high temperatures and preserved foods positively associated with increased pancreatic cancer risk.

Bariatric Surgery and How it May Decrease Cancer Risk

Several studies comparing obese individuals who have undergone bariatric surgery to non-surgical obese controls have found an association between bariatric surgery and decreased cancer risk. The effect appears to be stronger in women than men, which may be due to the fact that fewer men than women were included in the studies due to a strong female preponderance in uptake of bariatric procedures. However, for reasons that remain largely unclear, gender is also known to impact upon obesity-related cancer incidence, progression and mortality to varying degrees depending on the specific type of cancer involved.

Whilst it is generally assumed that bariatric procedures reduce cancer risk by promoting rapid weight loss, other mechanisms may be possible. In particular, studies across various species of animal have indicated that calorie restriction reduces risk of cancer mortality, so the strict regulation of caloric intake required following bariatric surgery may convey a more direct benefit in this regard. Dietary changes that lead to reduced intake of saturated fat, salt and processed meats, with increased consumption of fruit, vegetables and fiber are also associated with reduced cancer risk.

There is some limited evidence to suggest that the repetitive cycle of weight loss followed by weight gain observed in some people who try to lose weight through dieting may be associated with an increased risk of kidney cancer when compared to individuals with a stable weight. Whilst further research in this area is required, bariatric surgery is known to facilitate permanent weight loss in those who have previously struggled to maintain a healthy body weight through dieting alone, and may therefore act to mitigate any such risk.

For obese individuals with GERD, bariatric surgery can often lead to significant reduction in symptoms, potentially reducing the likelihood of developing Barrett’s esophagus and esophageal adenocarcinoma.