Link between obesity and cancer

Around one-fifth of cancer deaths in the United States are associated with obesity. But how is fat fueling the growth of tumors?

Most of the mice in Stephen Hursting’s laboratory at the University of Texas in Austin have cancer. However, among mice with identical genetics and the same tumor types, their cancers vary drastically; some have tumors bulging out of their sides, and others look healthy. The differences between the mice: their diets and the resulting amount of fat in their bodies. Hursting, a nutritional scientist, can quickly predict which mice have the most aggressive, fastest growing cancer by answering a simple question: Which mice are obese?

Ample evidence exists that fat animals are more likely to develop cancer than lean animals. Cancers in fat animals also grow faster and larger, spread more quickly, and are more resistant to treatment. Furthermore, although experiments explaining the molecular basis for the phenomenon have focused on rodents and monkeys, human cancer statistics suggest that the same holds true for us: overweight and obese people get more cancer, worse cancer, and die more often from cancer than people with less body fat.

In a landmark 2003 study, American Cancer Society researchers analyzed data on obesity and cancer from a group of 900,000 American adults that they had monitored for 16 years (1). The researchers found that the most obese women had a 62% increase in their risk of dying from cancer than women of normal weight; for obese men, the increase was 52%. The wide range of tumor types included colorectal, liver, gallbladder, pancreas, esophageal, kidney, prostate, breast, uterine, endometrial, and ovarian cancers. The researchers concluded that above-normal weight was associated with almost 20% of all cancer deaths in the United States. “There’s an incredibly powerful link between obesity and cancer,” says oncologist Joyce Slingerland of the University of Miami, Florida. “Everyone’s heard of obesity’s effect on heart disease and diabetes, and we’re now beginning to understand that the cancer risk is just as great,” she says.

Although researchers and epidemiologists had long suspected that diet and cancer were linked, efforts to explain why being fat makes cancer more deadly have only begun to deliver results in the past decade. As obesity rates soar around the world, there are still more questions than answers. However, researchers say there are now glimmers of hope: treatments that weaken the effects of obesity on cancer in mice, and a better fundamental understanding of how fat fuels cancer.

Sea of Fat Cells

At first, physicians thought the statistics on obesity and cancer could be explained by a

What we're learning is that fat cells provide a microenvironment that tumor cells really enjoy.

few simple facts. Cancer in obese people is often detected late, when a tumor is more advanced, and obese individuals are more likely to have complications from surgeries, such as those performed to remove or biopsy a tumor. However, a closer look at the numbers, along with studies of obese mice, made it clear that some other factor was at play.

For molecular biologist Mikhail Kolonin at the University of Texas Health Science Center in Houston, one hint came from the list of cancers that obese people are more likely to experience. “If you look at the meta-analysis of which cancers are affected by obesity, it’s the tumors in the abdominal cavity,” he says, “It’s those surrounded by a sea of fat cells.”

Lung cancer does not normally grow more often, or more quickly, in overweight mice or people. However, when Kolonin injected lung cancer cells into the side of a mouse’s abdomen, the cancer was suddenly affected by the mouse’s body fat levels, growing more aggressively in fatter mice. This result suggested that a location near fat reserves—not the underlying tumor genetics, or even body-wide obesity levels—was driving tumor growth. “What we’re learning is that fat cells provide a microenvironment that tumor cells really enjoy,” says biologist Philipp Scherer of the University of Texas Southwestern Medical Center.

In the 1990s, Scherer and other researchers found that fat cells, called adipocytes, are more than inert energy stores. Adipocytes produce hormones and other signaling molecules that affect the rest of the body. More fat means more of these signals. Some of the resulting signaling molecules act on the brain, regulating hunger, or damp down the mechanisms that produce fat cells. Other signals tell blood vessels to tunnel deeper into the fat tissue so that they can deliver oxygen to the extra cells. However, as someone becomes obese, the messages become garbled.

When fat cells cannot get enough oxygen, the fat tissue becomes thicker and recruits molecules from the immune system that cause inflammation: a desperate plea for new blood vessels that carry oxygen and nutrients to the tissue. “The environment that this fat tissue begins setting up is exactly the type of environment that cancer cells thrive in,” says Scherer.

Major Players

In the past few years, researchers hunting for the fat cells’ cancer-causing signals have narrowed in on a few prime suspects.

Hursting has discovered that rapamycin—a molecule known to increase the lifespan of mice—can slow the growth of tumors in obese mice. Insulin-like growth factor 1 (IGF1) has the opposite effect, speeding up tumor growth in dieting mice by activating the same pathway that rapamycin inhibits.

Rapamycin and IGF1 both affect a protein called mammalian target of rapamycin (mTOR): rapamycin turns it off, whereas the growth factor turns it on. mTOR is a master switch that controls how cells grow and use energy, and it makes sense, says Hursting, that fat tissue would influence this program. “What we’ve found is that in the obese state, several pathways feeding into mTOR are all really fired up,” he says, “It’s like a domino effect.”

Turning down these mTOR-activating pathways in obese people may offer a way to break the obesity-cancer link. “The good news is that in mice you can disconnect the obesity itself from the metabolic consequences of obesity in terms of the cancer risk,” Hursting says.

The adipocytes in an obese person turn on many cellular switches that increase mTOR levels, Hursting thinks. The mTOR then initiates its own programs, ones that help cells, including tumor cells, to grow. So when Hursting blocks mTOR in obese mice, their tumors no longer grow as fast (2). “mTOR has emerged as a major player in this field,” says Hursting. “It helps explain how several different aspects of fat and sugar metabolism impacting obesity and cancer biology are coming together into one pathway,” he says.

Scherer has focused on a different molecule produced by fat cells. Endotrophin is a small protein cleaved from collagen VI, which adipocytes produce for structural support and to recruit vital growth factors. Obese individuals, with more adipocytes, tend to have high levels of collagen VI.

Scherer previously found that, compared with normal mice, mice without collagen VI have smaller, slower-growing tumors that spread throughout the body less often. In 2012, Scherer’s team homed in on endotrophin as the root cause of that effect (3). When they increased levels of endotrophin in a line of mice prone to developing severe breast cancer, tumors grew even more quickly than usual and spread to the lungs faster. When Scherer administered a drug that blocked endotrophin, the mice’s tumors were smaller and less likely to spread.

Scherer is still trying to work out how endotrophin is cut from the larger collagen VI molecules, and how the peptide affects tumor cells, but he thinks it could hold the key to controlling obesity’s cancer connection. “We know that there’s probably no single magic bullet that will stop a tumor from growing or fat tissue from influencing cancer,” says Scherer. “But our hopes are high for endotrophin,” he says.

Two-Way Street

Although fat cells can influence tumor cells through molecules like mTOR and endotrophin, cancers are also likely to have a reciprocal effect on adipocytes.

Slingerland studies cytokines, immune molecules that are produced when growing fat reserves start to choke themselves, triggering inflammation to draw in oxygen and nutrients. The more obese someone is, the more cytokines are likely to be circulating in their body. Furthermore, the more cytokines someone with breast cancer has, Slingerland et al. have shown, the worse their cancer is likely to be (4). The association likely holds true for other tumor types, she thinks.

The fat cells are recruited to join the tumors and then become a part of their supporting cast.

However, Slingerland has also realized that the cytokines initially produced by adipocytes are the beginning of a dangerous synergy. “If you grow cancer cells together with fat cells,” explains Slingerland, “the fat cells encourage the cancer cells to produce more cytokines. But the cancer cells also coax the fat cells into making even more cytokines.”

In addition, cytokines not only help an established tumor grow, Slingerland says, they can also set loose cancer cells to establish new tumors. “If you happen to be a cancer cell that has escaped from the primary cancer site and moved into the fatty tissue surrounding it, you suddenly find yourself in this cesspool of cytokines that can enhance your ability to survive.”

Kolonin and colleagues have made a similarly troubling discovery: roaming tumor cells can even send out signals that coax fat cells to join them, supporting the nascent tumor wherever it lands (5). “The fat cells are recruited to join the tumors and then become a part of their supporting cast,” Kolonin says.

Fat Memories

The essence of all these molecular findings is this: the environment that adipocytes try to promote, to help them survive in thick layers of fatty tissue, is the same environment that helps tumor cells survive. That environment features lots of blood vessels, an ability to turn off signaling that could otherwise lead to cell death, and local inflammation that encourages new cell growth and a steady flow of nutrients to the area.

It’s too early to know what these findings mean for preventing and treating cancer in obese people, says Hursting. More work is needed to figure out what levels of weight loss, exercise, and diet might lower an overweight person’s cancer risk, for example. “Surprisingly, very little has actually been done where someone actually takes an obese population, brings their weight down, and looks at the cancer risk after that,” he says.

Hursting has studied this question in mice, however, and found that being overweight can leave a lasting impression on the body even after the fat has gone. When obese mice lost weight, most of the molecules in their body returned to levels seen in a lean animal. However, mTOR levels remained high (6). “There’s some memory there,” he says. “We don’t know how long that lasts yet, or whether we can erase it.” The finding suggests that individuals who are obese and lose weight might still have an increased risk of cancer.

Such studies have not yet been done in humans, but they could offer newly diagnosed cancer patients crucial information about whether losing weight will help their cancer survival odds, says Kolonin. “Going on a diet could actually put fat tissue under stress and add fuel to the fire,” he says.

In an ideal world, Slingerland says, the data on obesity and cancer would be the last straw needed to inspire obesity prevention efforts, especially aimed at youth. “We have all these overweight children now,” she says. “And these fat kids are going to grow up into fat adults and we’re going to have a greater burden of cancer.” To researchers, she says, the data are clear that obesity does not just lead to an increased risk of heart disease and metabolic syndrome, but cancer as well. The public, though, needs to hear this message loud and clear.