American Institute for Cancer Research 11th Annual Research Conference on Diet, Nutrition and Cancer

Transcription

1 American Institute for Cancer Research 11th Annual Research Conference on Diet, Nutrition and Cancer Diet, Nutrition and Cancer Prevention: Where Are We Going from Here? 1 Vay Liang W. Go, 2 Debra A. Wong and Ritva Butrum* UCLA Center for Human Nutrition, Los Angeles, CA and *American Institute for Cancer Research, Washington, DC. ABSTRACT Since the national declaration of the war on cancer three decades ago, research on carcinogenesis has yielded a tremendous knowledge base on cancer. Cancer cells are the result of multiple genetic defects resulting from exposure to environmental, dietary and infectious agents. Multistep and multistage carcinogenesis may span 20 y or more, a time that provides research and clinical opportunities to suppress this disease in its early and premalignant stages before clinical symptomatic, invasive stages. Where do we go from here? After this year s milestone of gene sequencing accomplishments, further research opportunities arise in pursuing studies on the mechanisms of the acquired capacities of cancer cells, including their limitless replicative potential, sustained angiogenesis and invasion and avoidance of apoptosis. With new DNA chip technology and functional proteomics, complex nutrient-gene interactions may now be investigated. Research on nutrient-gene interactions not only provides pathophysiologic mechanisms of cancer causation and prevention, but also improves the ability to conduct cancer surveillance, crucial in identifying at-risk populations. By combining chemoprevention approaches, from the use of single nutrients to multiple dietary constituents and functional foods, the scope of future cancer prevention strategies will be broadened. Research on eating behavior and changing dietary patterns must be included in any cancer prevention strategy. A new paradigm for diet, nutrition and cancer prevention can be developed using multidisciplinary approaches that include lifestyle and environmental changes, dietary modifications and physical activity consciousness to reduce the burden of cancer not only for high risk individuals but for the general population as well. J. Nutr. 131: 3121S 3126S, KEY WORDS: diet nutrition cancer prevention direction At the beginning of this new millennium, cancer remains the second leading cause of death in the United States and the leading cause of death among the most productive age group, i.e., those aged y. It is now estimated that nutrition and lifestyle factors may be determinants of up to 80% of large bowel, breast and prostate cancer cases and of one third of all cancer cases (1,2). The link between diet and cancer is now fully appreciated, and the NIH and the American Institute of Cancer Research (AICR) have addressed the research agenda. Indeed, we have come a long way since President Nixon s declaration of war on cancer three decades ago and the publication of Diet, Nutrition, and Cancer by the National Research Council of the National Academy of Sciences nearly two decades ago (3). AICR was founded just before publication of the report of the National Academy of Sciences with the sole purpose to foster research and educate the public about the diet-cancer connection. It subsequently expanded 1 Presented as part of the 11th Annual Research Conference on Diet, Nutrition and Cancer held in Washington, DC, July 16 17, This conference was sponsored by the American Institute for Cancer Research and was supported by the California Dried Plum Board, The Campbell Soup Company, General Mills, Lipton, Mead Johnson Nutritionals, Roche Vitamins Inc. and Vitasoy USA. Guest editors for this symposium publication were Ritva R. Butrum and Helen A. Norman, American Institute for Cancer Research, Washington, DC. 2 To whom correspondence should be addressed. vlwgo@ucla.edu. its mission to conduct research on diet and cancer prevention and treatment including their underlying mechanisms. AICR is now the third largest cancer charity in the United States and remains the only charity focusing solely on diet, nutrition and cancer prevention. This year s AICR 11th Annual Conference centered on these issues and focused on current aspects of state-of-the-art research on diet, nutrition and cancer prevention. These research areas include the molecular mechanism of action of the cancer preventive agents in phytochemicals, botanicals and nutrients present in the diet; the emerging genetic models used in studies on diet and cancer prevention; and specialized diets and nutritional supports of cancer patients and cancer survivors. For the first time, results of evidence-based dietary interventions in cancer prevention were presented. With the explosion of new knowledge in carcinogenesis, nutrient-gene interaction and evidencebased dietary intervention studies on cancer prevention, we will be able to develop a new paradigm and framework for a dietcancer prevention agenda. Our task this year was to discuss where we are going from here. To be able to answer this question, it is important to review where we have been and where we are now. Where have we been? In the late 1960s and early 1970s, most researchers centered their investigations on the virus hypothesis the concept that /01 $ American Society for Nutritional Sciences. 3121S

2 3122S SUPPLEMENT FIGURE 1 Serum immunodiagnosis bank slide file (# A, National Cancer Institute). The NCI research goal in the 1970s was for early diagnosis of cancer before it metastasized and became symptomatic. viruses or other infectious agents could alter cell metabolism, causing the uncontrollable growth of tumors that spread and lead to metastasis, malnutrition and ultimately death. At that time, the realization of an alarming 300,000 cancer deaths per year and public and scientific community support to combat the disease led to the declaration of a war on cancer, and Congress passed the National Cancer Act of 1971, which was signed into law by President Nixon (4). State-of-the-art cancer research became focused on cancer therapy and early diagnosis. The National Cancer Institute (NCI) developed the National Network of Cancer Centers to conduct various clinical trials to investigate the efficacy of chemotherapy and other therapeutic modalities as well as organ site task forces to address research agendas affecting particular cancer organ systems. Diagnosis was limited to histology while cancer staging was being developed and standardized. The clinical research goal focused on early diagnosis, before cancer spread and surgery became the main approach to curing cancer (Fig. 1). Cancer prevention and control strategies were limited, and the link between cancer and tobacco use and smoking was the key controversy. Awareness of other environmental carcinogens such as asbestos and toxic chemicals was growing. Twenty years ago, the NCI Cancer Commission of the National Academy of Sciences and the Committee on Diet, Nutrition, and Cancer published their report, Diet, Nutrition, and Cancer, through the NRC (3). This comprehensive report provided available evidence and the subsequent conclusion that most major cancer sites are influenced by dietary patterns. This report has led to various national recommendations on research agendas in the investigation of the diet-cancer link, including the expansion of basic research in molecular and cellular nutrition, the identification of foods and dietary constituents that can alter cancer risks and studies of the mechanisms by which these dietary constituents modulate cancer risks. The chronology of the highlights of national agendas in relation to the AICR mission is outlined in Table 1. The NCI research strategy did not specifically address cancer and diet and nutrition until 1983, when the Diet and Cancer Branch was established within the Division of Cancer Prevention and Control. The goals of the program, both intramural and extramural, have focused on conducting research in nutritional and molecular regulation, basic cellular mechanisms, prevention-related molecular epidemiology, clinical nutrition and dietary intervention trials to identify and validate cancer prevention dietary patterns and behavioral modification research. The NCI diet and chemoprevention research programs grew in size and scope (5). This action fostered the steady growth in the number of research projects and an increase in its level of support from $28 million in 1980 to $120 million in This is truly a small investment, given that NCI s budget was $4 billion (6). The historical perspective of the results of 30 y of cancer research was recently reviewed well by Groopman (7). In the 1980s, AICR was focusing its limited resources first on public education and then on pilot feasibility extramural research and fellowship programs supporting both basic and clinical diets, nutrition and cancer research. These programs supported new investigators in a seed program that allowed TABLE 1 Diet-cancer link: national highlights in relation to the American Institute for Cancer Research 1982 Diet, Nutrition, and Cancer, published by the National Research Council (NRC) and commissioned by the National Cancer Institute (NCI), concluded that cancers of most major sites are influenced by dietary patterns. Recently founded, the American Institute of Cancer Research (AICR) reprinted the report in book form and distributed it to 30,000 researchers and health providers Diet, Nutrition, and Cancer: Directions for Future Research (NRC) recommended creating a program to identify food constituents and their mechanisms of action in modulating cancer risk and developing methodology and data based on human exposure to relevant dietary constituents The Surgeon General s Report on Nutrition and Health emphasized basic science research into nutrition-related cancer prevention. AICR established its extramural research program The National Academy of Science s Diet and Health: Implications for Reducing Chronic Disease Risk stressed basic research in molecular and cellular nutrition and further exploration of the mechanisms by which foods and dietary constituents modulate cancer risk Healthy People 2000: Emphasized the linkage of nutrition and physical activity to cancer. AICR announced their first annual conference on Diet, Nutrition and Cancer prevention Bionutrition and Cancer Prevention Research Initiative Report by NCI suggested establishing an intramural program for nutrition research The Institute of Medicine s report Opportunities in the Nutrition and Food Sciences echoed previously suggested research themes Food, Nutrition and the Prevention of Cancer: A Global Perspective, published by the World Cancer Research Fund and AICR, summarized the scientific evidence regarding nutrition-related cancer prevention. The NCI Cancer Prevention Program Review Group recommended that prevention must be the principal component of the National Cancer Program NIH established the Center Program on Dietary Supplement Research: Botanicals. This program included investigation of the mechanisms of nutrient-gene interaction in cancer prevention. The NCI Nutrition Implementation Report redefined the goals and emphasis placed on nutrients and to diet as a whole and integrated knowledge and methods from all relevant areas of biological sciences AICR inaugurated the New American Plate. Presidential Summit on Promoting Healthy Eating and Active Living.

3 WHERE ARE WE GOING FROM HERE? 3123S FIGURE 2 Diagram illustrating the onset and progression of neoplasia through an intraepithelial phase to an invasive phase. The onset of intraepithelial neoplasia is heralded by a monoclonal expansion, which progresses via clonal evolution to the invasive phase (5). them to generate preliminary data for subsequent applications for funding from various federal and other funding agencies. These programs created a new pool of investigators focused on diet and cancer research. Subsequently over this past decade, AICR launched this symposium series, which has provided key platforms to discuss diet, nutrition and cancer. Sessions cover a diverse array of timely and critical issues in cancer prevention and treatment, thus allowing all attendees to participate in discussions matched to their individual interests and backgrounds. Issues related to the role of diet in cancer prevention and treatment are featured each year, including results of studies involving various foods, phytochemicals and nutrients; presentation of novel molecular mechanisms and genetic models; use of complementary and alternative approaches for prevention and treatment; optimal diets for those wishing to prevent cancer or its recurrence; and problems facing researchers who are designing future dietary studies. The proceedings from these symposia have been published in Advances in Experimental Medicine and Biology, with the exception of last year s and this year s symposia, published in The Journal of Nutrition. These conferences have emphasized the importance of multidisciplinary approaches to the investigation of underlying cellular and molecular mechanisms, clinical dietary modulations and interventions and experimental and clinical trials. Considerable scientific evidence supports the concept that nutritive and nonnutritive plant-based dietary factors can effectively prevent cancer. Where are we now? Ever since the national declaration of war on cancer three decades ago, research on carcinogenesis has yielded a tremendous knowledge base on cancer. Over the past 10 y, scientists have gained new insight into the fundamental nature of the cancer cell. Cancer cells are caused by multiple genetic defects that can result from exposure to environmental, dietary and lifestyle factors and infectious agents. The multistep, multistage process of gradual carcinogenetic changes in the biological behavior of a clonogenic population of cells may span years or decades. This process has been well investigated in common epithelial tumors. Among the epithelial cancers, such as colorectal, breast, prostate, lung, pancreas and others, a diffuse genomic instability after exposure to caustic agents and neoplastic clonal expansion starts at one or more sites in an epithelium and progresses independently at different sites (5). This leads to the development of preinvasive intraepithelial neoplasia. The onset of intraepithelial neoplasia is heralded by a monoclonal expansion, which progresses via clonal evolution. This neoplastic progression will lead to increases in both total bulk and extent of dissemination (known clinically as neoplasm increase in stage and grade in time) (Fig. 2). Cancer tissues are now viewed as complex tissues with heterotypic cell biology. Cancer cells acquire certain capacities to be self-sufficient in growth signals and insensitive to antigrowth signals, have limitless replicative potential, evade apoptosis, have sustained angiogenesis and lead to tissue invasion and metastasis (8) (Fig. 3). A molecular target along the multistep carcinogenesis continuum, with the development of appropriate magic bullets to halt carcinogenesis, has now become the focus in drug development, and some success has been achieved. An example is the recent development of ST1 571 (Gleevec) for chronic myelogenous leukemia. However, there is also multicentricity of intraepithelial neoplasia that can be dormant over the years. These characteristics provide opportunities for modulation by bioactive phytochemicals in diet. The national goal of cancer prevention programs is now focused on the need for dietary supplements, functional foods and drugs to prevent the onset of intraepithelial neoplasia or suppress or prevent its progression to invasive cancer (5), and the NCI and other funded agencies are conducting various chemopreventive clinical trials and dietary intervention studies (9). Two interrelated events led to the establishment of our FIGURE 3 Parallel pathways of tumorigenesis. All cancers must acquire the same six hallmark capabilities. The order in which these capabilities are acquired is likely to be quite variable across the spectrum of cancer types and subtypes. (8).

4 3124S SUPPLEMENT research agenda on diet and cancer today. AICR and the World Cancer Research Fund charged an international expert panel with the following goals: 1) to review the scientific and other expert literature linking food, nutrition, food processing, dietary patterns and related factors with the risk of human cancers from a global perspective; 2) to devise a series of dietary and other recommendations suitable for all societies to reduce the risk of cancers; and 3) to consider both the feasibility and policy implications of a global implementation of these recommendations. The NCI director and the chair of the NCI Board of Scientific Advisors also appointed a review group on cancer prevention research. Both reports were released in The AICR/WCRF (1) report provided a global perspective on diet, nutrition, and cancer prevention recommendations, whereas the NCI report provided a specific research agenda for diet, nutrition and cancer prevention (10). These two monumental accomplishments have lead to the acceleration of research on the diet-cancer link. The AICR/WCRF expert panel came to a scientific consensus that cancers are largely preventable and that the most effective means of reducing risks are avoiding tobacco use, consuming an appropriate diet and limiting exposure to occupational and other environmental carcinogens. The panel estimated that 30 40% of cancer cases throughout the world are preventable by feasible dietary means. The evidence is convincing or probable that diets high in vegetables and fruits protect against cancers of the mouth and pharynx, esophagus, stomach, colon and rectum, pancreas, lung, larynx, breast and bladder. Consumption of g/d or more of fruits and vegetables and a variety of fruits and vegetables could, by itself, decrease the overall incidence of cancer by at least 20%, if implemented over time. The panel further provided 14 public health goals and advice to individuals, inviting international and national agencies, industries, medical and health professionals, consumers and other organizations worldwide to join a public policy framework for a cancer prevention agenda. The AICR/WCRF reports have also provided the framework for research on the molecular mechanisms of dietary constituents in the carcinogenesis pathway from activation of procarcinogens to the initiation and promotion stages of carcinogenesis and to tissue invasion and metastasis. These documents also discuss areas in which other cancer-causing agents and risk factors act or interfere with dietary constituents, such as tobacco use, sedentary lifestyle, obesity, hormones and growth factors, radiation, environmental chemicals and infectious agents. This diet and cancer process relationship of the above factors is illustrated in Figure 4 and forms the basis of the rationale of ongoing molecular and cellular mechanistic research in this area. For example, dietary carcinogens such as N-nitroso compounds, polycyclic aromatic hydrocarbons and heterocyclic amines are present in cooked, cured or spoiled foods and some alcoholic drinks. The level of exposure of the cell DNA to those and other carcinogens depends largely on the general quality of diet; the presence of bioactivated dietary constituents, including antioxidant vitamins found in abundance in fruits and vegetables, counteracts the effect of these food carcinogens. In addition, normal cellular metabolism via the phase 1 metabolizing enzymes, which evolved to convert particular chemicals to more water-soluble compounds that can be excreted in the urine, can also create chemical carcinogens through a process called metabolic activation. Enzymes involved in this metabolic activation of chemical carcinogens are similar to those involved in detoxification reactions involving the oxidation, reduction and conjugation of drugs and hormones and smoke carcinogens. This system includes the cytochrome P 450 system. Phase 2 detoxification enzymes, such as glutathione S- and UDP-glucuronosyl transferases, are also involved in the processing of chemicals in food and can be induced by a variety of plant compounds. If these protective mechanisms are inadequate, the carcinogens introduced can form DNA adducts, which may result in somatic alterations of oncogenes, tumor suppressor genes or DNA-repair genes, leading to the initiation of carcinogenesis. During the promotion stage of carcinogenesis in which there is growth of the initiated clone of cells, energy balance and turnover are critical in maintaining normal cell behavior or expansion of the abnormal cells. In this stage, total energy intake and physical activities play a key role and probably mediate through the action of specific hormones and growth factors. Even at this stage, vegetables and fruits provide folate, a major source of physiologic methyl donors, reducing the likelihood of DNA hypomethylation and chromosome breakage. Fiber may be fermented by colonic bacteria, producing volatile fatty acids, which increase the probability for initiation and promotion of abnormal cells that have undergone apoptosis. The relationship of genetic polymorphisms of the metabolizing enzymes to nutrient-gene interaction, oxidative stress, hormone metabolism and carcinogenesis has been proposed by Heber and Go (11) in the xenobiotic hypothesis. This unified concept of diet and the cancer process provides a framework from which future research can be pursued. The NCI Cancer Prevention Program Review Group recommends that prevention must be a principal component of the National Cancer Program if the cancer burden is to be reduced. The group further concludes that over the next generation, far greater reduction in cancer mortality will come from prevention than from the various treatments that are currently available or will be available in the coming years. It is through the application of excellent basic, clinical and population-based research that effective preventive interventions can be mounted. The most significant accomplishment of the NCI Review Group is that they recommend opportunities for diet, nutrition and cancer prevention research at NCI. Specific recommendations are as follows: 1) encourage research to identify biomarkers of the consumption of key dietary components; 2) recommend an increase in the investment in research toward understanding the biological mechanisms underlying the putative diet and cancer association, particularly concerning fruits and vegetables, fatty acids and total energy consumption; 3) encourage methodological research on design and strategies for diet and cancer prevention intervention trials; and 4) recommend developing an orderly process for the development and testing of dietary behavioral trials on hypothesized healthy eating patterns. They also emphasized the development of animal models and extrapolation to human cancer prevention and genetic predisposition to cancer and detection of precursor lesions. This report was followed by the reorganization of the NCI Division of Cancer Prevention and led to various initiatives in research on diet and cancer along with various workshops, including the topic of genomics and nutrition, in setting the current research direction and funding for both basic and chemoprevention and dietary trials at NCI (7). Investigation into the dietary relationship to carcinogenesis will require a new knowledge base of genes and gene expression and proteomics of hormones, growth factors and metabolic enzymes as well as their interaction in cellular signal transduction mechanisms. In this century, the successes of sequencing human genes as well as plant genes are now in hand. The proliferation of new technologies in genomic and functional proteomics and expanding knowledge in the carci-

5 WHERE ARE WE GOING FROM HERE? 3125S FIGURE 4 Dietary factors, smoking, physical activity and obesity in relation to the carcinogenesis process, from the initiation and promotion stages to metastasis or apoptosis (1). nogenesis processes will allow us to better understand the role of nutrient-gene interaction in carcinogenesis that can develop the ultimate goal for a new discipline of preventive oncology. Where are we going from here? The war on cancer, after 30 y of effort, is only partially won. The age-adjusted cancer mortality rate has declined 1%/y, and the goal for a cure for cancer is far from accomplished. However, because of the knowledge we have gained of the carcinogenesis process and the role of dietary constituents on the effects of tumorigenesis processes, it is now a widely accepted concept that cancer is mostly a preventable disease. A new paradigm for diet and cancer prevention, research and strategy must be developed to include the nutrition modulation of the carcinogenesis pathway by nutrients, micronutrients and phytochemicals. This pathway includes nutrition modulation of DNA damage and repair mechanisms; DNA methylation pathways influencing gene expression and cellular phenotypes; antioxidant rearranging and oxidative stress modulation; target receptors and signaling pathways; cell cycle controls and check points; and antiangiogenic properties. This knowledge allows us to set the framework for diet and cancer prevention research that includes biomarkers of the consumption of key dietary compounds, research on biological mechanisms underlying putative diet and the cancer relationship, identification of the molecular targets of action by dietary constituents and development of the new paradigm for diet and cancer prevention research. For the past century, our current nutrition research paradigm has been based on identifying a single nutrient in a deficiency state and the role of particular single nutrients in cell growth and development of an organism as well as investigating their roles in the intermediary metabolism pathways. Our current knowledge points to the idea that diet contains multiple biologically active compounds and nutrients and nonnutritive compounds that can affect gene expression and have different bioavailability profiles and can be converted

6 3126S SUPPLEMENT into isomers and metabolites of different potency, which lead to complex beneficial interactions. This provides justification for us to create a new research paradigm in determining and investigating the diet in health promotion and disease prevention approaches, including cancer. The NIH, through the Office of Dietary Supplements, has already established a new paradigm in botanical research for disease prevention that can be adapted to cancer prevention. This paradigm includes defining the plant source genetically, growing the plant under specified conditions, establishing the range for phytochemical contents present, testing the plant extract in appropriate biological models, standardizing the extracts for clinical testing in phase 1 and 2 trials and building the science base for supplements. On the basis of this paradigm, we can build the approach to how to conduct appropriate diet interventional studies for cancer prevention both primary and secondary prevention. The populations to be studied include both cancer survivors and high risk populations, with appropriate biological markers, so that we can develop the evidence base for dietary intervention for cancer prevention similar to that presented by speakers on this panel. Hopefully, we can develop the evidence base for dietary intervention for cancer prevention useful for our practice and for public health policy recommendations. So, where do we go from here? After this year s milestone of gene sequencing, there arises further research opportunities in pursuing studies on the mechanisms of the acquired capacities of cancer cells, including their limitless replicative potential, sustained angiogenesis and invasion and avoidance of apoptosis. With new DNA chip technology and functional proteomics, complex nutrient-gene interactions can now be investigated. Research on nutrient-gene interactions not only provides pathophysiologic mechanisms of cancer causation and prevention, but also improves the ability to conduct the cancer surveillance that is crucial in identifying at-risk populations. By combining chemoprevention approaches using single nutrients with multiple dietary constituents and functional foods, the scope of the future cancer prevention strategies will be broadened. Research on eating behavior and changing dietary patterns as well as psychobiological approaches must be included in any cancer prevention strategy. New frameworks are to be developed logically, using multidisciplinary approaches that include lifestyle and environmental changes, dietary modifications and physical activity to reduce the burden of cancer for the general population as well as high risk individuals. Partnerships with industry, government and other agencies must take into consideration all other cultural, behavioral, social and other micro- and macroenvironments identified in last year s national Summit on Promoting Healthy Eating and Active Living, which are essential in developing a public policy framework for progress in diet and cancer prevention (12). LITERATURE CITED 1. World Cancer Research Fund and American Institute for Cancer Research (1997) Food, Nutrition and the Prevention of Cancer: A Global Perspective. American Institute for Cancer Research, Washington, DC. 2. U.S. Department of Health and Human Services (2000) Healthy People U.S. Government Printing Office, Washington, DC. 3. National Academy of Science (1982) Diet, Nutrition and Cancer. National Academy Press, Washington, DC. 4. National Cancer Act, P.L. # (1971). 5. Boone, C. W. & Kelloff, G. J. (1999) Cancer chemoprevention: subject cohorts with early neoplasia, agents, and intermediate marker endpoints in clinical trials evaluated by computer-assisted image analysis. In: Nutritional Oncology (Heber, D., Blackburn, G. L. & Go, V.L.W., eds.), pp Academic Press, San Diego, CA. 6. National Cancer Institute (1999) Report of the Nutrition Implementation Group New Directions for Nutritional Research at the National Cancer Institute. Available at Accessed August 8, Groopman, J. (2001) The thirty years war have we been fighting cancer the wrong way. The New Yorker 52 63, June 4, Hanahan, D. & Weinberg, R. A. (2000) The hallmarks of cancer. Cell 100: Greenwald, P., Clifford, C. K., McDonald, S. S. (1999) The challenge of cancer prevention and control: diet, nutrition and cancer prevention. In: Nutritional Oncology (Heber, D., Blackburn, G. L., Go, V.L.W., eds.), pp Academic Press, San Diego, CA. 10. National Cancer Institute (1997) Division of Cancer Prevention. National Cancer Institute Cancer Prevention Program Review Group Report. Available at htm. Accessed on August 7, Heber, D. & Go, V.L.W. (1999) Future directions in cancer and nutrition research: gene-nutrient interaction and the xenobiotic hypothesis. In: Nutritional Oncology (Heber, D., Blackburn, G. L, & Go, V.L.W., eds.), pp Academic Press, San Diego, CA. 12. Partnership to Promote Healthy Eating and Active Living (2001) Summit on promoting healthy eating and active living: developing a framework for progress. Nutr. Rev. 59: