"LET FOOD BE THY MEDICINE"

BY Eve Jacobs

Once cancer gains a foothold, its grip on an organ, or march through the body, can be relentless and deadly. We’ve all witnessed how it works. So it follows that no matter how potent a therapy is in demolishing a malignancy, it can never compete in effectiveness with preventing cancer’s inception, or halting it in the earliest stages before the tag of cancer can even be affixed to it. Unfortunately, the science of prevention and chemoprevention has had to play catch-up with surgery and drug therapies. For obvious reasons, researching what works to ward off cancer in the human body is a difficult and very tricky business. Newly out of its infancy, this discipline is now advancing steadily, but it’s already taking a hit from a disbelieving public. Let’s talk tomatoes. Carrots, celery, tea, peppers, oranges, barley and rye, too. The media coverage on food choices for a healthy heart, weight loss, younger-looking skin, mobile joints, a sharp memory is serving up far too much sometimes-conflicting information to absorb and digest. Now add to that daily updates on what may work to head off cancer. No wonder we’re in the throes of a steak and potatoes backlash.

What does science really know about cancer prevention?

Quite a bit. Researchers now tell us that many cancers are preventable, although not all, of course. The 5 percent that are familial and the 2 percent triggered by pollution are the most difficult to avoid. "Causes of the majority of the other 93 percent are behavior-related," says Elisa Bandera, MD, PhD, assistant professor of epidemiology at UMDNJ’s Robert Wood Johnson Medical School (RWJMS) and School of Public Health. She says that 30 percent of cancers in the U.S. are attributed to tobacco, 30 percent to diet, 5 percent to infection, 5 percent to a sedentary lifestyle, 5 percent to occupation, 3 percent to alcohol and 3 percent to reproductive factors. Bandera emphasizes that these figures show that our choices can have a significant impact on whether we develop cancer.

That’s very good news. "Basically, if you quit smoking, drink moderately, keep your weight in check, exercise regularly, protect yourself from the sun and you and your partner from sexually transmitted diseases, and eat a healthy diet, then your risk of developing cancer is vastly diminished," she explains.

The million dollar question is: Which dietary factors protect us and which may promote the development of cancer? Scientists now agree that choosing a plant-based diet and whole grains rather than refined grains and sugars is the way to go. What have been standards in the American diet—pasta, white rice, white bread, potatoes, sweets, red meat and butter—are now allocated to the tip of the new food pyramid developed by Dr. Walter Willett, an expert in nutritional epidemiology at Harvard’s School of Public Health, indicating their intake should be "sparing." Perhaps surprising to many are the recommendations that dairy products be limited to one to two servings per day and fish, poultry and eggs consumed no more than twice daily.

Vegetables and fruits are key to the new food pyramid, which promotes five servings daily. Whole grains are recommended for consumption at most meals, nuts and legumes one to three times daily, and plant oils, including olive, canola, soy, corn, sunflower, and peanut oils, are urged for cooking and dressings. Monosaturated oils (as well as the fat in certain fish) are among the foods thought to be protective against some cancers.

Eating five servings of fruit and vegetables is not that difficult. A single serving from this category might constitute one glass of orange juice, one cup of salad, half a cup of chopped vegetables or a medium-sized piece of fruit. Bandera, who has conducted and published several studies on the relationship of diet, alcohol consumption and cancer, says that eating a variety of such foods is recommended since they contain a broad spectrum of vitamins, minerals, antioxidants and other "phytonutrients" known or thought to be anti-carcinogenic.

According to Bandera, foods documented as cancer-promoting include red meats, particularly grilled, which have been linked to cancers of the rectum, colon, prostate, breast and pancreas; alcohol, which she says is "clearly related" to cancers of the mouth and pharynx, larynx, esophagus, liver, colon and rectum, breast and possibly lung; and high sodium foods, among them canned soup and "lunchables" because sodium can cause stomach cancer.

Excess weight is now thought to be a major player in promoting cancer. The connection between obesity and cancers of the endometrium and colon, and postmenopausal breast cancer, are well-established. But a recent study by the American Cancer Society, published in the April 24 issue of The New England Journal of Medicine, links excess weight to almost all cancers. The 16-year study following 900,000 men and women found that the risk of cancers of the colon, rectum, esophagus, pancreas, kidney, gallbladder, ovary, cervix, liver and prostate, as well as multiple myeloma and non-Hodgkins lymphoma, escalated in those who were overweight; and that the amount of excess weight was directly related to the risk of death from these cancers. The authors point to "potential biological mechanisms that include increased levels of endogenous hormones—sex steroids, insulin and insulin-like Growth Factor I— associated with overweight and obesity."

Bandera, who is also a graduate faculty member at Rutgers, is particularly concerned about children and teenagers, because she says that research now indicates that what a child eats may have an impact on the development of breast cancer later in life and that early influences may reach as far back as the intrauterine environment. She says the mother’s diet during pregnancy, her weight gain, and whether she smokes and drinks alcohol may all have long-range influence on a child’s risk for cancer in subsequent years.

"Trying to prevent breast cancer as an adult may not be possible because most risk factors for the disease can not be changed at that time," she says. "We are looking at early life exposures, even at prenatal exposure to hormones and other factors. It is well known that early onset of menses increases the risk of breast cancer. In order to have an impact in breast cancer prevention, we probably need to intervene before puberty, both to try to postpone the onset of menses and because the breast is most susceptible to environmental factors between puberty and when a woman has her first child."

A long-term British study corroborates her views. It found that children who regularly consume too many calories have an increased risk of developing cancer as adults. Higher birth weight has also been linked to breast cancer. A study by Bandera and colleagues at the University of Buffalo found that being breastfed as an infant was associated with a decreased risk of developing breast cancer as an adult.

The natural tie-in with calorie intake is exercise level, for both children and adults. Obesity has as much to do with food choices and amounts as it does with a sedentary lifestyle. New guidelines call for a minimum of 30 minutes of moderate exercise at least five times weekly, with 45 minutes of moderate to vigorous exercise daily being optimal. "Energy balance is the secret," says Bandera. "Eat less and exercise more."

Besides burning calories, the American Cancer Society says this level of physical activity may protect against cancers of the breast, colon and other sites by decreasing "the exposure of breast tissue to estrogen" and "improving energy metabolism," as well as reducing "circulating concentrations of insulin and related growth factors."

The nutrition and cancer expert says that many factors interact to determine whether a person will develop cancer or not. "Science is constantly evolving and we are learning in the process," she says. "That is why what you read in the press regarding diet and cancer prevention often seems confusing. What we do know is that a healthy diet and lifestyle can significantly reduce your risk of developing cancer and also help you fight the disease."

She stresses that findings from one single study should be viewed with caution: "You need to look at the whole body of evidence from experimental, clinical and epidemiological studies before you can say that x causes y. No single study will give you the whole picture."

Bandera is the recipient of a Cancer Prevention, Control and Population Sciences Career Development Award from the National Cancer Institute, which includes funding for a study examining the effect of diet—focusing on the role of phytoestrogens and alcohol—on endometrial cancer risk. She is collaborating with cancer epidemiologists from Memorial Sloan Kettering Cancer Center and the New Jersey Department of Health and Senior Services to recruit 400 women who have had a diagnosis of endometrial cancer and 400 "healthy" controls (who have never had an incidence of this type of cancer) to answer a nine-page questionnaire on intake of all kinds of foods, alcohol, and supplements. The study—which also looks at the role of estrogens and polymorphisms in genes involved in estrogen metabolism—will continue collecting data for two more years and is still recruiting participants.

In June, Bandera and her collaborators are planning to launch a similar study on ovarian cancer sponsored by The Cancer Institute of New Jersey (CINJ). They’ll recruit 300 women who have had ovarian cancer and compare their answers to questions on dietary intake, reproductive factors, obesity, and medical and family history to those of 300 controls. In addition, they’ll take a sample of cells from the mouth of each participant for a DNA study to try to determine genetic differences, with a particular focus on DNA repair genes. Cases and controls in both studies are New Jersey residents.

Bandera also has a strong interest in translating research findings into public health action. She is a member of CINJ’s Cancer Prevention and Control Program and vice chair of the Cancer Prevention Control and Advisory Group of the New Jersey Commission on Cancer Research. Working with the Department of Health and Senior Services, the researcher is leading the implementation of nutrition and physical activity goals as part of the state’s comprehensive cancer control plan. As a first step, Bandera, with collaborator Lisa Paddock, MPH, recently conducted a survey of nutrition and physical activity programs in the state and developed a resource guide and database available on the NJ Commission on Cancer Research Web site. The main goals of the plan are to promote longterm healthy eating patterns and healthy weight and physical activity, to boost research on effective dietary and physical activity approaches to prevent cancer, to increase survivorship of cancer patients and to assure their proper nutritional care.

"Despite national campaigns on cancer prevention, fruit and vegetable consumption is low, while the prevalence of overweight and obesity, and physical inactivity, is high among New Jersey’s residents," she says.

In closing Bandera notes the link between diet and health is nothing new, as she quotes Hippocrates’ advice from 431 B.C., "Let food be thy medicine…." and adds two words of her own, "choose wisely."

Observational vs. Investigational Research

Down the street from Bandera’s office is the laboratory suite of Steven Shiff, MD, a gastroenterologist, RWJMS associate professor and member of CINJ, whose research on the link between diet and cancer takes a very different track. While Bandera collects data from large groups to search for links between certain behaviors and particular cancers, Shiff’s approach is experimental. He and advanced practice nurse Rita Musanti, APRN-BC, AOCN, actually test promising substances to decipher the biochemistry of their action as cancer preventatives.

"The problem with epidemiological evidence is that you show associations but not causality,"says Shiff. "For instance, there is some evidence that red meat—beef, lamb and pork— may contribute to colon cancer development, but it’s not conclusive. This gives us things to investigate in prospective studies."

He points out that a 20- to 30-year trial of the effects of diet on humans is impossible to do, and that animal studies don’t necessarily match what happens in the human body. "Fundamentally, that is the real problem of why we are so confused about which dietary and environmental factors contribute to cancer," he states.

Because these longterm studies are not feasible, Shiff explains that researchers settle for "third best," which is short-term trials looking at the effects of a food or drug on an organ or system. In colon cancer research, which is his focus, Shiff says the goal is to intervene at some point in the decades-long development of a small premalignant lesion into full-blown cancer. Recent studies indicate that consuming calcium supplements regularly over a period of years or daily intake of aspirin or a nonsteroidal anti-inflammatory lower the risk of developing colon cancer or having a recurrence after an initial episode.

The researcher says he has three major research goals: to identify dietary factors or drugs that can safely prevent colorectal cancer in humans; to refine the methods used to test these agents in short-term trials; and to better understand how these agents prevent carcinogenesis at the cellular and molecular levels. Agents of interest to Shiff and collaborators at UMDNJ include: curcumin, the substance that causes the yellow color in mustard and curry, which has been shown to prevent colon cancer in animal models and acts as an anti-inflammatory; Quercetin, a substance found in apples, cranberries and onions; orange peel extract, which has a chemical structure similar to curcumin; sulindac, a nonsteroidal anti-inflammatory drug; and green tea and black tea, which have demonstrated anti-cancer effects in animal models.

Shiff is conducting short-term trials to test whether these agents can lower the risk of developing colon cancer. Participants are first evaluated and screened for pre-existing conditions which could skew the trials’ results, such as polyps, intestinal inflammation and small premalignant lesions. Volunteers are then examined via flexible sigmoidoscopy, to visualize the rectum and colon, and a biopsy of the inside lining of the intestine is taken to provide baseline tissue samples. Both tests are repeated at various intervals during the trials.

Although a few weeks or months seems too short a period to measure the anti-cancer effects of such agents, Shiff says that "the lining of the intestine is one of the most highly proliferative organs of the body, completely replacing itself every 7 to 14 days," and that anything taken into the body may affect this rate of proliferation.

"I’m pursuing the hypothesis that the total number of cells in the lining of the intestine is tightly regulated, roughly governed by the amount of cell renewal (proliferation) and cell loss (cell death). "Cancer involves disrupted regulation of the number of cells," he explains. "Increased proliferation or decreased cell loss tips the balance toward cancer development."

Because cancer takes 20 to 30 years to develop, Shiff says short-term studies require the establishment of biomarker endpoints (BEs), which should "indicate with reasonable accuracy the risk of future cancer development in an organ of interest such as the colorectum." He points to cholesterol level as a BE used by health care professionals to predict cardiovascular disease risk in a patient. Although several BEs are currently in use to predict a higher risk for colorectal cancer, the researcher says none of them is ideal and identifying new ones is a goal of his laboratory. BE measures used by the investigator on tissue samples include epithelial cell kinetics (proliferation or apoptosis), and gene or protein expression studies. Future plans include the use of microarray technology for genome analyses.

The researcher and his team are working to develop model systems for short-term trials to investigate blocking cancer development in many different organ systems. With UMDNJ collaborators, they are studying: if selenium can prevent a recurrence of stage 1 lung cancer; the effect of green tea on premalignant oral lesions; and whether after drinking green tea, its ingredients can be found in the prostate.

Our state ranks fourth nationwide in deaths from colorectal cancer. "We’re convinced that diet plays a role," says Shiff. His research could conceivably save thousands of New Jersey lives each year.