Reducing the Weight of Cancer Risk

Obesity wreaks havoc on the human body. This much we know. Obese men and women have high rates of type 2 diabetes, heart disease and stroke. Perhaps less commonly known is that obesity also increases the risk of developing cancer. In the United States, as many as 90,000 people die each year from cancers, like colon, prostate and breast, associated with being obese.

With more than two-thirds of adults in the U.S. overweight, more than one-third considered obese, and the numbers climbing ever higher, understanding the biology behind the cancer and obesity association is becoming increasingly critical.

Drs. Susan Perkins, Stephen Hursting and Nomelí Nuñez (left to right) dig deep into the genes, molecules, hormones and cellular processes that could be causing cancer in people with weight problems.

“Obesity is a major concern in the quest to prevent cancer,” says Dr. Stephen Hursting, a professor of nutritional sciences whose research has focused on the obesity-cancer link for the past 15 years. “We’re interested in this because disrupting the obesity-cancer connection could have a huge impact on reducing the suffering and death from cancer in this country.”

To get to the bottom of the obesity-cancer problem, Hursting and his colleagues, like Drs. Susan Perkins and Nomelí Nuñez, assistant professors of nutritional sciences, are digging deep into the genes, molecules, hormones and cellular processes that could be causing cancer in people with weight problems. They’re also looking at how lifestyle factors like exercise and diet interact with these molecular processes to prevent or promote cancer.

Watching weight

Hursting, Perkins and Nuñez study mice. Fat mice, lean mice, diabetic mice and mice that like to exercise their little hearts out.

“Our approach has been to mimic in mice the tumors showing up in people,” says Hursting, who arrived last year along with Perkins and Nuñez to The University of Texas at Austin from the National Cancer Institute. He is also a professor of carcinogenesis at the University of Texas M.D. Anderson Cancer Center.

“Once we characterize the mice in terms of cancer development, we bring in lifestyle. We have them diet, gain weight and exercise and look at the impact on the cancer process. Then, we delve into this molecularly.”

It’s pretty clear that diet affects tumor development. Hursting has looked at the obesity-cancer link in mice that are genetically predisposed to get cancer, much like some humans. When the mice were placed on diets that restrict their caloric intake—what Hursting calls “Weight Watchers for mice”—they show a marked decrease in the onset of cancer.

What processes might be changing at the molecular level to slow the progression of cancer with a calorie restricted diet? Or perhaps more important, what things are happening inside an obese person’s body that promote cancer?

Molecules behind the madness

Fat cells naturally produce some chemicals that could promote cancer when they are present in the body in excess. Take, for example, the molecule leptin, which is produced by fat cells and is called the “fat hormone.” Leptin is what tells the brain it’s had enough to eat, and Hursting’s work suggests leptin can also promote the growth of some cancer (but not normal) cells. And because obese people are saddled with more fat cells, they have unusually high levels of leptin. (Paradoxically, the leptin is not doing its job telling obese individuals that they should stop eating, a phenomenon called leptin resistance.)

Hursting and his colleagues have found that when mice are put on a calorie-restricted diet, the amount of leptin circulating in their blood goes down along with risk of developing tumors.

Another molecule that Hursting has found shows a marked decrease when mice consume fewer calories is called insulin-like growth factor-1 (IGF-1). IGF-1 regulates cell growth and death, and in humans, a high level of IGF-1 in the blood is associated with greater risk of cancer.

“IGF-1 and leptin are key parts of the cancer-obesity equation,” says Hursting.

“Our goal is to identify targets that we can disrupt,” he says. “We recognize that not everyone can run five miles a day or have a drastic change in diet. But if we can identify those targets that are important, then perhaps we can disrupt the link between cancer and obesity. IGF-1 and leptin, and the proteins with which they interact, are good targets for disruption.”

But the obesity-cancer story is slightly more complex, to say the least.

Nuñez says fat cells and the molecules they produce aren’t the only things that feed into the obesity-cancer equation. There are a whole host of other changes the body experiences related to obesity, most notably changes related to type 2 diabetes (formerly known as adult-onset diabetes before an astonishing number of obese children began getting it).

Type 2 diabetics are resistant to insulin, which means that the cells in their bodies don’t respond appropriately to the hormone that regulates levels of glucose in the blood. Diabetics also have increased levels of inflammation, which is like a constant low-level immune response in the body. Inflammation is associated with many diseases such as cardiovascular disease and cancer. (Aspirin, an anti-inflammatory drug, decreases breast and colon cancer risk.)

Diabetes and cancer

To begin to see what role insulin resistance and inflammation might be playing in the obesity-cancer picture, Nuñez, Perkins and Hursting recently looked at tumor development in mice that were type 2 diabetic but genetically altered to have no fat. They used these “fatless” mice as a model for human breast cancer, looking at tumor development in mice mammary glands.

The scientists found that even though the fat cells weren’t there, the mice developed tumors anyway.

“We showed that fat cells aren’t required to influence breast cancer,” says Nuñez. “The presence of insulin resistance and inflammation (processes associated with obesity and diabetes) in our fatless mice is responsible for increasing the risk for cancer. If we’re going to prevent breast cancer in obese people, then we’re probably going to want to target inflammation and insulin resistance, rather than the fat.”

Given that between 30 and 50 percent of breast cancer deaths in the U.S. can be attributed to excess body weight, these findings are significant.

Leptin and IGF-1 contribute to insulin resistance and are surely playing a role in some cancers, but it’s also becoming clear that inflammation is not to be ignored.

“This is exciting for us,” says Nuñez. “Now we’re getting a little bit closer to finding the pathways we can target to prevent many cancers.”

Energy balance

No matter which way you look at it, obesity is related to taking more energy into the body than is being used up. The excess energy is stored as fat.

“We want energy balance,” says Hursting. “Our energy intake should equal our energy output. As a nation, we’re not doing a great job at that. Many of us are consistently in positive energy balance, leading to weight gain.”

One process we can do something about, says Perkins, is physical activity—burning calories through exercise. But what effect will exercise have on cancer? In recent studies, Perkins and Hursting found that exercise slowed the progression of colon cancer in mice, but not as well calorie restriction.

Looking at the genes that might be affected by exercise and diet, Perkins and Hursting found that the genes that are turning on or off during exercise are very different from those that change when calories are restricted. The work is preliminary, but Perkins says that eventually this might help researchers develop strategies for reducing cancer with a combination of diet, exercise and pharmacology (using medicines to target specific genes).

Nuñez sees obesity as a huge problem in and of itself, but he also sees it as a lens that magnifies processes leading to cancer in general. (He’s also looking at the effects of drinking alcohol on cancer and the relationship between cancer and wound healing.)

“Obesity allows us to see things more clearly,” he explains. “When you look at the system essentially under normal conditions, there are only small effects of insulin, leptin inflammation, etc. But obesity amplifies the processes that lead to cancer, allowing us to see it more clearly. Once we amplify it, we can find the targets.”

(www.utexas.edu)