Nutrition Action Health Letter

September 7, 2007

Cancers of the breast, colon, esophagus, kidney, uterus. In 2002, the International Agency for Research on Cancer concluded that people who are overweight or obese have a higher risk of all five. Now there's evidence for more.

"I would add gallbladder, liver, pancreas, and advanced prostate cancers to the list," says Eugenia Calle, an expert on cancer and obesity at the American Cancer Society. Extra pounds account for an estimated 20 percent of all cancer deaths in the United States. And the percentage is growing...because Americans are growing.

"We're seeing cancers now linked to obesity that we haven't seen in the past," says Susan Taylor Mayne of Yale University. "And that's scary because of the high prevalence of overweight and obesity."

Our expanding national waistline could reverse some of the progress that we've made against cancer, she adds.

"Rates of cancer mortality have been declining because of gains in tobacco control," says Mayne. "But we can lose that headway if we lose the war on obesity."

Why are researchers seeing a stronger link between obesity and cancer than in the past? "We may not have picked up a link 20 years ago because fewer people were overweight 20 years ago," says Yale's Susan Taylor Mayne.

For example, experts estimate that in the United States, excess weight explains roughly:

* half of all uterine and esophageal cancer,

* a fifth (in women) to a third {in men) of all colorectal cancer,

* a third of all kidney cancer,

* a quarter of all pancreatic cancer, and * more than a fifth of all postmenopausal breast cancer.

But in Europe, where obesity rates are lower-like ours were 20 years ago-excess weight explains a lower percentage of most cancers.

"The list of cancers related to obesity is growing," says Mayne. "It's alarming."

How much of a spare tire do you need before your risk climbs? It depends. For some cancers, risk starts to rise even before you cross the line that defines "overweight."

"With breast, colon, and endometrial cancer, you can see an increase in risk at the high end of the normal-weight range compared to the low end," says the American Cancer Society's Eugenia Calle. "And then the risk increases in an almost linear fashion from the very lean to the very heavy."

That's partly because the "normal-weight" range is quite large. "Two people of the same height could be 30 to 50 pounds apart and still be normal weight," she explains.

For some cancers, only heavier people appear to be at risk. "For example, it seems like there's no increase in the risk of pancreatic cancer until you get very heavy," says Galle. But that may simply reflect incomplete data.

"Most studies have used Body Mass Index, or BMI, as a measure of obesity, and that's not the best measure for all cancers," she says. "For example, now we're looking at waist circumference and pancreatic cancer and finding a stronger effect."

The lengthening list of cancers linked to obesity, says Mayne, suggests that "it may be a systemic effect."

That's because fat tissue isn't just dormant storage space. It's an active organ, releasing and receiving signals from other organs.

So far, three main theories explain how those signals may help turn healthy cells into tumors.

I. The Insulin Pathway

Insulin is the hormone that allows blood sugar to enter cells, where it is either burned for energy or stored as fat.

But if you have too many overstuffed fat cells, they can become resistant to insulin. It's as though the cells were trying to shut the door that would let in even more sugar.

With insulin losing its punch, the pancreas ramps up its output of the hormone.

"If you have more or bigger fat cells on board, the pancreas is forced to produce more insulin," says Michael Leitzmann, an epidemiologist at the National Cancer Institute.

High insulin levels are especially likely if you have what experts call "central obesity".

"These are people who have an apple-shaped body with a big waist instead of the pear-shaped people with big hips," explains Karen Margolis of the University of Minnesota and HealthPartners Rest-arch Foundation in Minneapolis.

It's clear that insulin resistance increases the risk of diabetes and heart disease. Now cancer may join those ranks.

"It's likely that the insulin pathway and insulin resistance are important for cancers of the colon, liver, pancreas, and kidney," says Calle.

How? Insulin prompts the body to make insulin-like growth factor (IGF-I). In test tubes, both insulin and IGF-I make cells proliferate.

"Insulin itself stimulates growth, so it could act directly on cancer cells," says researcher Edward Giovannucci of the Harvard School of Public Health. "And insulin sensitizes the cells to IGF-I."

It's not that overweight people necessarily have more IGF-I. Rather, "insulin decreases IGF-I binding protein, so there's more free IGF-I in the blood," he explains.

Here's what researchers know about cancers linked to the insulin pathway.

* Liver. "Peripheral fat in the thighs and hips-where a lot of women carry their fat - is not that metabolically active," says Calle.

On the other hand, the "visceral" fat around the waist is constantly sending out signals that promote inflammation or growth elsewhere in the body.

(Inflammation, which is often outwardly invisible, is the immune system's attempt to fight off and repair the damage caused by germs, irritants, or other insults.)

"We're not talking about the subcutaneous layer of fat between the skin and muscles," adds Calle. "We're talking about the fat behind the muscle wall that surrounds the organs."

"People don't realize that once you get beyond a certain level of adiposity, fat starts to infiltrate muscle and organs like the liver."

In the past, excess alcohol accounted for most fatty livers. "But the most common cause of abnormal liver tests in the United States now is non-alcoholic fatty liver disease," says Calle.

A fatty liver starts out benign, but it can lead to cell injury, scarring, and inflammation. "It can progress from fatty liver to hepatitis to cirrhosis to liver cancer," says Calle.

So far, studies suggest that the obese have anywhere from 1 ½ to 4 times the risk of liver cancer. But the disease is still rare in the United States, so it's harder to get a precise risk estimate.

* Colon. Colon cancer isn't rare. It kills more non-smokers than any other cancer.

In the National Institutes of Health-AARP Diet and Health Study, which tracked more than 300,000 men and 200,000 women for five years, the heaviest men had twice the risk of colon cancer, while the heaviest women had a 50 percent increase in risk. But that doesn't mean that everyone else is in the clear.

"The risk increases even for people who are mildly overweight, which isn't reassuring for people who have a couple of extra pounds," explains the National Cancer Institute's Michael Leitzmann.

Why does obesity seem to matter more in men than women? Fat around your waist is the culprit, and men are more likely to gain weight there.

Giovannucci and colleagues found that men with a waist measuring at least 43 inches had a 2 times greater risk of colon cancer than men with a waist smaller than 35 inches. And a big belly often goes hand in hand with excess insulin.

In human and animal studies, insulin levels are correlated with risk," says ovannucci. For example, the higher a person's insulin level, the more its colon cells roliferate.

"The data linking insulin to risk is stronger for colon than for any other cancer," says Giovannucci.

* Pancreas. Pancreatic cancer is deadly. Only one in five patients is alive one year after diagnosis, and only one in 25 survives five years. The only known risk factors are cigarette smoking, diabetes, and obesity.

"In the past six years, a huge number of studies using prospective data have shown a very strong association between obesity and pancreatic cancer," says researcher Dominique Michaud of the Harvard School of Public Health.

In most studies, being obese doubles the risk. "For people who are overweight, the link isn't as strong as it is for other cancers," says Michaud. "It shows up more for the obese."

A few studies, like the European Prospective Investigation into Cancer and Nutrition (EPIC), which tracked more than 430,000 men and women for six years, found a stronger link with waist size than with obesity per se.* But other than EPIC, "there's very little data on waist circumference," Michaud notes.

It's still not clear how excess fat leads to pancreatic tumors. "It's probably a consequence of sustained higher levels of glucose and insulin in the blood," suggests Michaud.

Inflammation may also play a role, she adds, "because people who are obese have higher levels of inflammation."

Again, it's the visceral fat cells deep in the belly that appear to be at fault. "Those fat cells are different," Michaud explains. "They're actively causing trouble."

* Kidney. Although kidney cancer accounts for only about 2 percent of cancer deaths, the incidence is rising in the United States and worldwide. Smoking, diabetes, high blood pressure, and obesity all seem to raise the risk, but it's not clear if a large waist matters more than a large number on the bathroom scale.

In many studies, excess fat anywhere in the body raised the risk. But in the Women's Health Initiative, which tracked about 140,000 U.S. women for nearly eight years, those with the largest waists (for a given hip size) had double the risk.

"Central obesity was the strongest risk factor in these women," says the University of Minnesota's Karen Margolis, who co-authored the study.

What's more, U.S. women who had lost or gained over 10 pounds more than 10 times during their lifetime had a 2 times greater risk of kidney cancer than those with stable weights.

"It appears that weight cycling has a pretty strong relationship with kidney cancer, particularly at the extreme," says Margolis. "But we don't know why."

II. The Estrogen Pathway

If you're overweight but don't carry the extra pounds in your waist, are you off the hook?

No. Fat-whether it's around your hips, thighs, waist, or wherever-produces steroid hormones like cstrogen.

"Another main way that obesity can raise the risk of cancer is through the estrogen pathway," says the American Cancer Society's Eugenia Calle.

In premenopausal women, estrogen comes largely from the ovaries. "After the ovaries stop functioning, the primary source of estrogen production is fat tissue," Calle explains. "And estrogen is associated with endometrial and breast cancer."

As with IGF-I, obesity depresses levels of binding proteins.

"There's not as much sex-hormone-binding globulin levels in the circulation, so less estrogen is bound" and free estrogen goes up, says Calle. And that increases risk. Some specifies:

* Breast. The risk of postmenopausal breast cancer rises by 30 percent in overweight women and SU percent in obese women. For years, researchers couldn't detect the link because they didn't separate women who take estrogen pills from those who don't.

"Weight is not related to breast cancer in postmenopausal women who take hormones," says Calle. That's because the pills raise estrogen levels-and the risk of cancer-whether the women are skinny or plump.

"The sharp decline in the number of women taking postmenopausal hormones means that weight matters to an increasing segment of the population," she adds.

More than other cancers, postmenopausal breast cancer is related to how much weight you gain as an adult. "That's in part because obesity may lower the risk of breast cancer in premenopausal women," says Calle.

Why? Obesity seems to impair their ability to ovulate. "So the woman with the highest risk was normal weight and had regular periods when she was young and became obese when she got older," Calle explains.

In a study of 44,000 postmenopausal women who weren't taking estrogen, those who gained 21 to 40 pounds after age 18 had a 68 percent higher risk of breast cancer that spread beyond the breast than those who gained 20 pounds or less. The risk was nearly double for those who gained 41 to 60 pounds and triple for those who gained more than 60 pounds.

"Excess adiposity is an important contributor to breast cancer risk in postmenopausal women, especially for tumors that are most likely to spread," says Calle.

* Uterus. Cancer of the endometrium (the lining of the uterus) is twice as likely in overweight women and 3 times more likely in obese than in normal-weight women.'

"That was the first cancer we recognized as related to obesity," says Calle. And it's clear why excess fat threatens the uterus. "We know that endometrial cancer is associated with estrogen that's unopposed by progestin."

Decades ago, researchers found that women who took estrogen pills had a higher risk of uterine cancer, but the risk disappeared in women who took estrogen combined with progestin.

Recently, researchers have detected a higher risk among women with central obesity. In a study of 223,000 European women, the risk of uterine cancer in those with at least a 35-inch waist was 76 percent higher than in those with a waist smaller than 32 inches.

"Once you get to some level of obesity, you're going to have a certain amount of central adiposity no matter where you carry your weight," says Calle.

III. Local Impact

For some cancers, obesity seems to boost risk because it leads to problems in nearby tissues (rather than by altering circulating hormones). For example:

* Esophagus. Two distinct cancers show up in the esophagus. With a five-year survival rate of 16 percent, both are deadly.

But there are differences. The incidence of squamous cell carcinoma (which is common in alcoholics, who are often underweight) is flat or dropping, while rates of adenocarcinoma (which is common in the overweight) are on the upswing.

"The incidence of adenocarcinoma is going up more in men than in women and no one knows why," says Yale's Susan Taylor Mayne. Obesity may have more impact in men, she suggests.

At first, researchers thought that a wider girth led to esophageal cancer because it caused acid from the stomach to flow back into the esophagus, causing inflammation.

"Obesity may be acting to promote cancer in part via acid reflux, but it may also be acting independently," says Mayne.

"In our study, when we controlled for reflux, we still found a strong effect of obesity, so risk is not just driven through reflux."

* Gallbladder. The gallbladder is a pear-shaped organ below the liver that collects and stores bile (a fluid made by the liver to digest fat). In about a quarter of all cases, gallbladder cancer is found early (usually when the organ is removed for other reasons), and the five-year survival rate is 80 percent.

But more often, the tumor is discovered too late to be surgically removed. If that happens, only 5 percent of patients live for two years.

While gallbladder cancer is rare, excess weight accounts for more than a third of all cases in the United States. How?

"Obesity is associated with gallbladder stones," explains Calle. "The stones provide a local inflammatory environment," which sets the stage for cancer.

Uncertain Pathways

Researchers are still in the dark about how obesity may raise the risk of some cancers. For example:

* Prostate. Prostate cancer strikes one out of six men sometime in their lifetime. But only one in 34 dies of the disease.

Researchers saw no consistent link with weight until they separated men with local, less aggressive cancers from those with more aggressive or fatal cancers.

"Obesity is associated only with the more aggressive prostate cancers," says Harvard's Edward Giovannucci. "So it's possible that obesity doesn't cause prostate cancer, hut makes prostate cancer more likely to progress."

For example, when researchers followed more than 28S1(K)O men from the National Institutes of Health-AARI1 Diet and Health Study for five years, the risk of dying of prostate cancer was 2.S percent higher in those who were overweight than in those who were normal weight. And the risk was twice as high in the most obese men.

Among the possible explanations: "Obesity may increase the blood supply to the tumor or increased growth factors like insulin could cause it to progress," suggests Giovannucci. "Or it's possible that not all prostate cancers are alike."

In other words, aggressive cancers may have a different cause than those that don't spread.

"It looks like there are at least two distinct types of prostate cancer," explains the National Cancer Institute's Michael Leitzmann.

"We can separate them according to the grade-how abnormal the cancer cells are-and according to the stage-whether they've spread beyond the prostate gland or not."

And obesity may promote only the aggressive (higher grade, higher stage) cancers. In fact, excess fat may protect against localized prostate can- cers-those "you'll die with, not from," says Leitzmann.

Why? Higher levels of insulin, free IGF-I, and lcptin (a hormone that's secreted by fat cells) are potential culprits. So is testosterone.

"Heavy men have lower testosterone levels," explains Leitzmann. "We know that testosterone leads to the start of prostate cancer."

Hut testosterone also helps maintain the structure and function of the prostate cells. "So the cells are more likely to go awry if testosterone levels are low."

That's speculative, he adds. "But it's possible that high testosterone levels make you more likely to get the disease, but low testosterone levels make the disease worse once you get it."

(C) 2007 Nutrition Action Health Letter. via ProQuest Information and Learning Company; All Rights Reserved