We've known for a long time that a high-fat diet, obesity and lack of exercise can increase the risk of developing heart disease and type 2 diabetes, two conditions that affect millions of Americans. What we are finding out now is that those same lifestyle factors also play an important role in cancer. That's the bad news. The good news is that you can do something about your lifestyle. If we grew thinner, exercised regularly, avoided diets rich in red meat (substituting poultry, fish or vegetable sources of protein) and ate diets rich in fruits and vegetables, and stopped using tobacco, we would prevent 70 percent of all cancers.
The strongest evidence of the importance of lifestyle in cancer is that most common cancers arise at dramatically different rates in different parts of the globe. Several cancers that are extremely common in the United States—colon, prostate and breast cancer—are relatively rare in other parts of the world, occurring only 1/10th or 1/20th as often. Equally striking, when people migrate from other parts of the world to the United States, within a generation their cancer rates approach those of us whose families have lived in this country for a long time. Even if people in other parts of the world stay put, but adopt a U.S. lifestyle, their risk of cancer rises; as Japanese have embraced Western habits, their rates of colon, breast and prostate cancer have skyrocketed.
What is it about our lifestyle that raises the risk of many types of cancer? The main culprits seem to be the Western diet, obesity and physical inactivity. While we've known about the importance of tobacco and cancer for more than 50 years, we are just beginning to understand how diet, a healthy body weight and regular exercise can protect us against cancer.
A striking example of the profound influence of diet was reported last summer in The Journal of the American Medical Association. Doctors determined the eating habits of patients with colon cancer in the years following surgical removal of the cancer. Over the next five years, those who ate a traditional Western diet had a threefold greater likelihood of developing a recurrence of the disease than did those who ate a "prudent" diet rich in fruits and vegetables and including only small amounts of red meat. How had diet affected these patients? The surgery clearly had not removed all their colon-cancer cells: prior to the surgery, some cells had already spread from the primary tumor. The Western diet had somehow stimulated the growth of these small deposits of residual cancer cells.
Obesity is the second most important factor in causing cancer in Western populations after tobacco, and there is evidence that maintaining a healthy weight is protective against the disease. A study by the American Cancer Society in 2003 found that the heaviest people, in comparison with the leanest, had a significantly increased risk of death from 10 different kinds of cancer in men, and from 12 different kinds in women. The most extreme examples were liver cancer in men (nearly fivefold increased risk) and uterine cancer in women (more than sixfold increased risk).
Exercise has also been shown to play an important role in protecting against some cancers. For example, the Nurses' Health Study reported that women who had one or more hours per day of moderate exercise had a 30 percent lower risk of colon cancer than women who exercised less. Exercise protects against breast cancer, as well.
Lifestyle influences a person's risk for cancer by generating growth-promoting signals that affect cells primed to become cancerous, or that already are cancerous. What primes those cells to become cancerous in the first place are changes in their genes.
All tumors begin with one renegade cell. Initially the cell is just one of about 30 trillion or so in the body. It looks no different from the cells around it, and, like those cells, it divides only if the organ it's part of needs it to divide. Then, even though the organ around it has enough cells, the renegade cell begins to multiply uncontrollably: one cell becomes two, two become four, four become eight, until the descendants are beyond counting.
Cancer is ultimately a disease of malfunctioning genes. Perhaps 10 percent of all cancers occur in people who have inherited genes that make them vulnerable. In some cases, those genes are so influential the risk of cancer is very high. However, most of us are born with good genes that succeed in flawlessly organizing our growth and development. After all, our genes have been optimized by more than 600 million years of evolution; they ought to work well. During the course of our lifetimes, though, genes are damaged in various cells throughout the body. It is these mutated genes that drive most cancers.
Every cell contains growth-promoting genes called "proto-oncogenes" and growth-stopping genes called "tumor suppressor" genes. Mutations that activate a proto-oncogene can cause the gene to release an unceasing stream of growth-stimulating molecular signals that cause the cell to multiply. Conversely, mutations that inactivate tumor-suppressor genes cause their growth-stopping messages to be silenced. In most human-cancer cells, there are multiple mutations—some that activate oncogenes and some that silence tumor-suppressor genes. In other words, cancer cells have stuck accelerator pedals and faulty brakes. During our lifetime, the cells in our bodies will divide 1016 times—that's 10,000 trillion times—creating 10,000 trillion opportunities for our "start" and "stop" signals to malfunction, and for a tumor to start.
Another important gene, called telomerase, is turned off in healthy cells, causing the cells to die after they have doubled about 50 times. Telomerase is turned on, however, in many cancer cells, which allows them to multiply indefinitely. There are other genes that cause a cell to "commit suicide" when the cell senses that it has been damaged; if such a cell suicide gene becomes disabled, a cancer cell will be allowed to multiply.
Genes also affect a cancerous cell's ability to metastasize—to detach itself from the primary tumor, crawl through the walls of nearby small blood or lymph vessels and spread through the circulation to other parts of the body. Research published in the past year has identified sets of genes that normally are active only when cells in an embryo need to migrate from one part of the embryo to another. In cancer cells that metastasize, these long-silent genes have somehow been activated. The genes make it easy for a cell to detach itself from the tissue around it and they improve the cell's ability to move toward and through the walls of blood and lymph vessels. Recently, a small molecule called microRNA-10b was discovered to powerfully affect the ability of breast-cancer cells to metastasize. This is exciting because, at least theoretically, such small molecules are attractive targets for treatments.
But what causes the various genetic changes that lead to cancer? Mutation-inducing chemicals—mutagens—in our environment can do so. Exhibit A, of course, is tobacco smoke. However, other environmental chemicals that many people suspect of causing cancer—food preservatives, contaminants in our drinking water, pollutants pouring out of smokestacks—rarely do so. In fact, in the developed nations, only 1 to 2 percent of cancers are attributable to such environmental pollutants.
Instead, most cancer-inducing mutations occur when cells damage their own genes accidentally. Each of our cells continuously produces mutation-inducing chemicals as byproducts of its normal metabolism. When our cells generate energy by converting oxygen into water, modified oxygen molecules called "oxygen radicals" are produced. These radicals strike wildly at all the molecules in our cells, including the DNA of our genes. Although our cells have the ability to repair this damage, the protection is not perfect, and so mutations and mutant genes accumulate as we grow older.
Mutations, while necessary, are not sufficient. Something else—something from outside the cancer cell—needs to fan the flames. A cell with several mutations may be primed to become cancerous, or may even be in the sluggish early stages of cancer, but that cell usually needs to be stimulated by additional growth-promoting signals to become a full-blown tumor. In fact, development of the great majority of human cancers is likely to be driven by these non-mutagenic "cancer promoting" molecular signals.
We don't know precisely how the Western diet increases our risk of cancer. The foods we eat contain chemicals that can mutate genes and that therefore could cause cancer. For example, red meat cooked at high temperatures generates potent mutagens called heterocyclic amines. Foods contain many different chemicals, and those chemicals are transformed in our body into many other chemicals, making it very difficult to pinpoint just what it is about the Western diet that raises our risk of cancer. But there is no doubt that it does.
While we don't really understand yet why obesity fosters cancer, cancer promoters could play a role. Obesity leads to high levels of insulin-like growth factor (IGF-1) in the circulation: theoretically, this could protect early-stage cancer cells scattered throughout the body from dying, since insulin-like growth factor inhibits the action of cell suicide genes. Inflammation also may explain the link between obesity and cancer. Inflammation is a normal body process designed to rid a tissue of infection and to heal it following injury. Cells of the immune system orchestrate inflammation, and some of the weapons they deploy are chemical signals called cytokines. Often, inflammation is brief. If your skin is cut, or develops a bacterial infection, inflammation aids in repairing the wound or eliminating the bacteria. Having done its job, inflammation then subsides.
However, if you have a condition that inflammation cannot rapidly heal, then the inflammation becomes protracted, chronic. The injured tissue is constantly bathed in growth-promoting cytokines that tell stem cells in the tissue to begin multiplying, in order to replace the cells that have been injured and destroyed. If any of these stem cells already have acquired mutations that make them precancerous, cytokines that encourage those cells to multiply can increase the risk that a tumor will start. For example, stomach tissue that can turn cancerous when it is chronically inflamed in response to the bacteria that cause many stomach ulcers. The same thing happens to the lining of gallbladders after years of irritation from gallstones, or to the liver after years of infection with hepatitis viruses.
What does inflammation have to do with obesity? Fat cells release inflammatory chemicals into the circulation that can stimulate the growth of cancer cells. The more overweight we are, the greater the level of inflammatory signals. It is possible that these cytokines act as cancer promoters, but much more research is needed to determine whether that is true.
Regular moderate exercise lowers the levels of both IGF-1 and cytokines in our blood, and it does so even if the exercise does not lead to a healthy weight. It is possible that the lowered levels of these cancer promoters are one explanation for the protective effect of regular exercise. Blood-estrogen levels are lowered by regular exercise in women, and this may be another way that regular exercise protects against getting breast cancer.
Our growing understanding of cancer genes, and how they are influenced by cancer-promoting chemical signals, already has led to important new diagnostic tests and powerful new treatments, and will likely lead to even more important advances in the future. But epidemiological studies of lifestyle and cancer have given us the power, today, to reduce our risk of cancer. While it isn't easy to make changes in lifestyle, it can happen. There are many fewer people using tobacco in the United States today than two generations ago, when the risks of tobacco were first revealed. It may take another two generations to further reduce tobacco use, and to improve our diets, weight and exercise patterns, but it can happen. If it does, our grandchildren are likely to look back at our generation, scratch their heads and wonder why it took so long for us to escape the disease that many of us feared the most, by simple changes in the way we led our lives.