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Obesity and Cancer: Complex Interplay of Multiple Factors


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The evolving concept that dietary fat plays an important role in the etiology of human cancer emerged more than 50 years ago. Ernst Wynder, MD, whose seminal epidemiologic work led to identifying smoking as a contributory cause of lung cancer, presented a paper in 1967 showing a decided correlation worldwide between high colon cancer rates and the high consumption of animal fats.1

However, numerous studies disputed the correlation between a high-fat diet and cancer. For instance, a 1981 paper in Cancer Research by American epidemiologist James Enstrom concluded that the “epidemiological evidence with regard to dietary fat and cancers such as colon and breast is contradictory and comes nowhere near satisfying the criteria for causality.”2

After decades of exhaustive research, the correlation between fat and cancer has been scientifically established. A 2016 review from a working group assembled by the International Agency for Research on Cancer linked overweight or obesity to a higher risk of 16 different cancers.3 And according to the Centers for Disease Control and Prevention, overweight- and obesity-related cancers now account for about 40% of all cancers.4

Mechanism Not Fully Understood

Although the role of lipids in tumor development and progression is not fully understood, promising new research is rapidly accelerating our knowledge in this important line of scientific inquiry, which could translate into clinical advances. A study published in late 2017 in

Cornelia M. Ulrich, PhD

Cornelia M. Ulrich, PhD

Cancer Prevention Research examined how fat affects carcinogenesis.5 One of the authors of this study, Cornelia M. Ulrich, PhD, Director of the Comprehensive Cancer Center, Huntsman Cancer Institute, University of Utah, Salt Lake City, told The ASCO Post that she and her associates conducted a literature review of PubMed/Medline, covering publications from January 1946 to March 2017, in studies that explored crosstalk between adipose tissues and carcinomas.

“There were about 20 primary research publications that mostly addressed this topic in studies looking at breast cancer and prostate cancer, but very little in other tumors,” Dr. Ulrich noted.

Tumor Crosstalk

According to Dr. Ulrich, carcinogenesis can depend upon “crosstalk,” or the various ways that cells react when the same signal is shared by more than one signaling pathway in two different cell types. “We believe that adipocytes are part of a specific tissue. For example, the breasts have a lot of adipose tissue, and the omentum surrounding the colon in the abdominal cavity is also dense with adipose tissue. However, our research indicates that fat tissue is not only a storage organ for lipids, but also an active endocrine organ that secretes adipokines and other inflammatory substances that can potentially affect tumor growth,” she shared.

She continued: “We also believe that when the adipocytes become part of the tumor microenvironment, the tumors themselves upregulate factors that solicit substances from the adipose tissues, which also accelerate carcinogenesis.”

There are multiple causal factors with obesity that have made it the number two risk factor for cancer after smoking.
— Cornelia M. Ulrich, PhD

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Dr. Ulrich was a member of the International Agency for Research on Cancer that examined the linkage between adiposity and cancer,3 and she said that the number of cancers associated with adiposity is now up to 16, including some brain tumors. The International Agency for Research on Cancer will soon release a formal report on its findings.

“It’s important to note that there are a multitude of mechanisms that affect the hallmarks of cancer, and there are vast differences in adipose tissue that can be more proinflammatory or less so. Inflammation depends on the type of adipose tissue and where it is located. For example, we’ve found that visceral adipose tissue is generally more proinflammatory.” 

Along with inflammation, Dr. Ulrich stressed there are a multitude of ways obesity can affect carcinogenesis. “Obesity results in the dysregulation of insulin/IGF1 signaling, raises estrogen levels, can adversely affect the immune system, can result in a decreased ability to repair DNA, and can also affect a person’s microbiome. All these factors can influence cancer susceptibility or progression,” she explained. “There are also multiple causal factors with obesity that have made it the number two risk factor for cancer after smoking.”

‘Very Different on the Inside’

Adipose tissue is found mainly under the skin but also in deposits between the muscles, in the intestines and in their membrane folds, around the heart, and elsewhere. “We are beginning to understand the specific roles of adipose tissue in carcinogenesis in areas around the body,” shared Dr. Ulrich. The innovative theme of crosstalk was highlighted in a symposium at the 2017 American Association for Cancer Research (AACR) Annual Meeting.6 “The work is extremely important, but we are just scratching the surface,” she added.

Dr. Ulrich emphasized that you cannot tell from observation how much adipose tissue a person has viscerally or subcutaneously. “People can be equally overweight on the outside, but they might look very different on the inside. Because fat exists both under the skin and deeper inside the body, even slender people may have excess fat surrounding internal organs. Healthy diets and exercise that includes strength training to build lean muscle mass can help fight the development of excess fat. To establish baselines of adipose tissue in different individuals, we need enhanced imaging techniques and biofeedback tools,” she proposed.

Multifactorial Issue

Although smoking-related lung cancer is still the number one cancer killer, obesity is now considered the second most preventable cause of cancer, not to mention a host of other morbidities related to obesity. Given that grim prognosis, it would seem that a national war on obesity, modeled on the successful public health initiative on smoking cessation, should be enacted. However, according to international obesity expert Donna Ryan, MD, Professor Emerita at Pennington Biomedical Research Center, Baton Rouge, Louisiana, although smoking is a single-source, easy-to-identify carcinogen, the drivers behind the obesity epidemic are multifactorial and challenging to identify.

Donna Ryan, MD

Donna Ryan, MD

Speaking with The ASCO Post, Dr. Ryan said: “Obesity is a worldwide epidemic, but the United States has clearly led the way. The National Health and Nutrition Examination Survey, which took place in the late 1980s with results released in the 1990s, found a dramatic increase in the prevalence of obesity. Before that period, the level of obesity was static for about a century, at less than 20%. Moreover, it’s not that there has been a gain of 5 or 10 pounds in the population that shifted the prevalence of obesiy, it’s that there has been a skewing of the population distribution. This means that if you look at the distribution of body mass index, the bell-shaped curve has been skewed upward on the right side, indicating a rise in severe obesity in the population. This means that there is a portion of the population that is at highest risk for obesity.”

Obesity is a psychological and physiologic disease. It is much more complicated than a ‘calories in, calories out’ formula.
— Donna Ryan, MD

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Asked what we know about the cause of obesity, Dr. Ryan replied: “The conventional wisdom is that certain people have a genetic susceptibility that is expressed by living in an obesogenic environment. And over the past several decades, there have been dramatic changes in the food supply, with the ready availability of energy-dense, highly palatable food. At the same time, we’ve seen a reduction in the need for physical activity. Research indicates that only 20% of today’s jobs require moderate physical exertion, compared with 50% of jobs in the 1960s. In short, about 80% of Americans don’t get enough exercise.”

Dr. Ryan also singled out poor sleep, stress, lower rates of breastfeeding, and medications such as antidepressants as potential reasons behind weight gain. Interestingly, the rise in the use of antidepressants seems to correlate with the rise in obesity. In the 1980s, 1 in 50 Americans used these medications, whereas the current estimation is 1 in 9.7

Epigenetics

According to Dr. Ryan, epigenetics plays a role in obesity risk. “We believe that prenatal life and infancy are very important in programming the development of obesity and other chronic diseases in adulthood. Nutritional deprivation during pregnancy, and at the other end of the spectrum gaining excessive weight during pregnancy, are risk factors for driving a U-shaped relationship for the risk of obesity in adulthood. It becomes a transgenerational problem; if you have more obesity in segments of the population, it drives the nutritional programming into their offspring,” she revealed.

MORE ON OBESITY AND CANCER

For more information on the link between obesity and cancer risk, see the special feature “Tackling the Obesity and Cancer Epidemic” in the May 25, 2017, issue of The ASCO Post. View online at www.ascopost.com.

 

Dr. Ryan noted that combating obesity is a much more complex challenge than smoking cessation programs, for instance. “We can’t expect to prevent our way out of this health crisis with public awareness campaigns about the health dangers associated with obesity. It is much more complicated than a ‘calories in, calories out’ formula. Obesity is a psychological and physiologic disease. Once individuals develop obesity, weight loss is resisted and weight regain after loss is promoted by physiologic and biologic adaptations that mimic the response to starvation. I think we need to recognize obesity as a complex chronic disease. Environmental changes and treatment programs are both important.”

More Specialists Needed

“We need more obesity specialists,” encouraged Dr. Ryan. “For instance, the American Board of Obesity Medicine certifies physicians in the treatment of obesity. They have certified about 2,700 members, and these physicians are knowledgeable about managing obesity. Sometimes it takes medication, and we may need to get over the diet-pill stigma. Bariatric surgery may also be needed. And payers need to cover medical and surgical weight management. Many plans still exclude obesity management treatment, and it’s unacceptable. The country is facing a massive public health crisis, and we need to honestly address the causes of and treatments for obesity.” ■

DISCLOSURE: Dr. Ulrich reported no conflicts of interest. Dr. Ryan has served as a consultant to Amgen, Sanofi, Novo Nordisk,
Orexigen, Eisai, IFA Celtic, Real Appeal, Gila Therapeutics, Scientific Intake, Baro Novo, and Epitomee; and has equity in Gila Therapeutics, Scientific Intake, and Epitomee, start-up companies in the drug and device sectors.

REFERENCES

1. Wynder EL, Shigematsu T: Environmental factors of cancer of the colon and rectum. Cancer 20:1520-1561, 1967.

2. Enstrom JE: Reassessment of the role of dietary fat in cancer etiology. Cancer Res 41(9 pt 2):3722-3723, 1981.

3. Lauby-Secretan B, Scoccianti C, Loomis D, et al: Body fatness and cancer: Viewpoint of the IARC Working Group. N Engl J Med 375:794-798, 2016.

4. Centers for Disease Control and Prevention: Cancers Associated with Overweight and Obesity Make up 40 percent of Cancers Diagnosed in the United States. Available at https://www.cdc.gov/media/releases/2017/p1003-vs-cancer-obesity.html. Accessed August 3, 2018.

5. Himbert C, Delphan M, Scherer D, et al: Signals from the adipose microenvironment and the obesity link: A systematic review. Cancer Prev Res (Phila) 10:494-506, 2017.

6. Ulrich CM: The adipose-cancer link: From microenvironment to metabolomics. 2017 AACR Annual Meeting. Abstract SY28-02.

7. Centers for Disease Control and Prevention. National Center for Health Statistics. Antidepressant Use Among Persons Aged 12 and Over: United States, 2011-2014. Available at www.cdc.gov/nchs/products/databriefs/db283.htm. Accessed August 6, 2018.


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