Uncovering the Mechanisms Linking Obesity and Cancer Risk || NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute

Uncovering the Mechanisms Linking Obesity and Cancer Risk

Being overweight or obese is associated with an increased risk for many types of cancer, including postmenopausal breast cancer; endometrial cancer; and colorectal, esophageal, gallbladder, kidney, pancreatic, and thyroid cancer. These risks are not minor. In 2002, the International Agency for Research on Cancer, using European data, estimated that obesity contributed to more than one-third of endometrial and esophageal cancer cases and a quarter of kidney cancer cases. (See the table below.)
Being overweight or obese also raises the risk of dying of cancer. In an often-cited paper published in 2003 in the New England Journal of Medicine, researchers from the American Cancer Society estimated that 14 percent of all cancer deaths in men and 20 percent in women could be blamed on excess weight.

Type of Cancer	Estimated Percentage Caused by Obesity
Endometrial	39
Esophageal	37
Kidney	25
Colon	11
Postmenopausal Breast	9
Source: Weight Control and Physical Activity, International Agency for Research on Cancer.

The obvious question is: Why? What biological processes mediate the relationship between excess body fat and increased cancer risk? Researchers are only beginning to tease out the answers, but almost all the factors under study are rooted in the fact that adipose (fat storage) tissue is highly metabolically active. Once thought to be just a passive storage depot for fuel, adipose tissue is now known to pump out an astounding array of hormones, growth factors, and signaling molecules, all of which can influence the behavior of other cells in the body.
Excess Hormones, Extra Risk
Most, if not all, of the molecules being studied as potential mediators between obesity and cancer are not cancer-causing but cancer-promoting. That is, they do not cause the mutations that turn a normal cell into a cancerous cell, but instead feed the growth and proliferation of malignant cells.
One of the best understood of the pathways that may lead from obesity to cancer involves the hormone estrogen, which fuels a large number of breast and endometrial cancers. In postmenopausal women, the levels of estrogen circulating in the bloodstream normally drop drastically, as the ovaries stop producing the hormone.
But fat tissue also produces estrogen, through a cellular pathway involving the enzyme aromatase, the target of several breast cancer therapies called aromatase inhibitors. In obese women, "the body fat just becomes an estrogen-producing machine," explained Dr. Leslie Bernstein, director of the Division of Cancer Etiology at City of Hope Comprehensive Cancer Center, who has studied the relationship between estrogen and cancer risk for years through the California Teachers Study.
This excess estrogen produced by fat can feed cancer cells that express the estrogen receptor. But estrogen alone does not account for all of the extra risk for these cancers in obese postmenopausal women. Another likely player in many types of cancer, including breast, colorectal, and pancreatic cancer, is insulin, the hormone that triggers cells in the body to take up glucose (sugar) from the bloodstream.

Obesity often goes hand in hand with type II diabetes and insulin resistance, which may contribute to cancer risk.

Obesity often goes hand in hand with metabolic syndrome and type II diabetes. In type II diabetes, the body's cells stop responding to insulin, causing a buildup of glucose in the blood, which in turn stimulates the body to produce even more insulin. And in some cancers, "insulin acts as a mitogen—it makes cancers grow faster," said Dr. Michael Pollak, director of the Division of Cancer Prevention at McGill University in Montreal.
Interestingly, a diabetes drug called metformin, which lowers the levels of blood glucose, has shown some anticancer activity. Several studies have suggested that people with diabetes who took metformin had a lower risk of developing cancer or dying from the disease compared with diabetics who did not take metformin. Currently, several clinical trials, including one in breast cancer, are testing the addition of metformin to standard treatment.
It will be important, stressed Dr. Pollak, to continue basic science research on metformin, given the many unanswered questions about who should take the drug. "I think this is an extremely promising area of cancer research, but we need to do more basic science research before we'll be able to design the best clinical trials" to figure out which patients are most likely to benefit from the drug, he said.
For example, other diabetes drugs lower insulin levels but don't show a similar anticancer effect, suggesting that metformin may affect more than just the insulin pathway. Also, some patients' tumors have mutations in the insulin signaling pathway that make the cells act as if extra insulin is always present, even when it's not. In these cases, reducing insulin would be futile in terms of cancer control. "So maybe those patients shouldn't be on clinical trials of metformin," said Dr. Pollak.
Digging Deeper
A myriad of other molecules are being studied to see if they contribute to the relationship between obesity and cancer. Some of these molecules, such as certain interleukins, are part of the body's natural inflammatory response, which is often chronically overstimulated in people who are obese. Others are signaling molecules called adipokines (cytokines produced by fat tissue), levels of which can be affected by weight gain.
Within NCI, researchers in the Division of Cancer Epidemiology and Genetics (DCEG) are using several multimarker panels to study molecular pathways that may link obesity to cancer risk in humans. Two panels—one that assesses 15 different estrogens and estrogen metabolites, and one that assesses 79 molecular markers of inflammation—are already being used to examine these mechanisms.
A third, more experimental panel simultaneously tests 400 to 600 small molecules to give a snapshot of metabolism at the time of sample collection, said Dr. Steve Moore, a research fellow in DCEG's Nutrition Epidemiology Branch. With these panels, "you can look at how the markers are related to cancer risk, you can look at how obesity is related to cancer risk, and you can look at how obesity is related to cancer risk after adjusting for the marker levels," explained Dr. Moore. "So by triangulating these three things, you can estimate which molecular mechanisms obesity is most likely to act through."
Other researchers are examining genetic variants that might also influence how obesity and cancer risk intersect. "A lot of people have looked at biomarkers like insulin, but what are the [full] genetic and molecular pathways being affected by obesity?" asked Dr. Li Li, associate director for Prevention Research at Case Comprehensive Cancer Center, Case Western Reserve University. His project, supported by the first tranche of Transdisciplinary Research on Energetics and Cancer (TREC) funding, is looking at how genetic variants found naturally in the population influence whether obesity can promote colon polyp formation.
All of this research may eventually help create targeted cancer prevention measures and treatments for overweight and obese patients, based on a better understanding of the molecular events driving progression. For now, "I would say what we know now supports the adoption of a healthier lifestyle that promotes weight control," concluded Dr. Moore.
—Sharon Reynolds
NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute