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Institute of Human Nutrition, University of Southampton, Southampton, UK
3To whom correspondence should be addressed. E-mail: aaj{at}soton.ac.uk.
ABSTRACT
Cells, individuals, and societies are complex systems in which the integrity of structure and function is protected through tight regulation and control. For each level of organization, health represents the ability to maintain integrity in response to the wider environment. Critical stages during growth and development act as checkpoints, where choice is exercised, and help determine future direction. Important among factors influencing the checkpoints include the availability of nutrients or foods within the immediate environment. At the cellular and whole-body levels, this information can be communicated to future generations. Recent work on the developmental origins of adult disease indicate specific factors that set limits on structure and function and potentially limit the capacity of the cell and individual to respond to environmental stressors that represent potential risk factors for neoplastic change. Epigenetic mechanisms modulate structure and function at the cellular and tissue levels, reflecting the potential for the growth and development of individuals, and reflect the food and nutrients available to the body as a whole and within the wider society. Understanding the nature and the interaction of the critical factors that determine and regulate variable stable and unstable gene expression will be increasingly important in characterizing abnormal cellular function and risk of disease for individuals and populations. This will require the ability to synthesize large data sets within and between different levels of organization to develop and refine a deeper understanding of how the systems are effectively integrated and regulated within and across generations and where this fails in the genesis of cancer.
KEY WORDS: • cellular microenvironment • epigenetic change • fetal origins of adult disease • body composition • metabolic programming
The fundamental nature of the cancer process is that of cellular derangement in which there is disordered regulation and control of normal cell cycling (1). Cells become autonomous in their behavior and no longer respond appropriately to the usual regulatory processes imposed either by internal cues or those coming from the environment. A very large body of information shows the many ways in which changes in the environment can lead to structural damage or altered cellular control. Furthermore, there are multiple exposures at different levels of organization—the molecule, cell, tissue, whole body, and wider society—that may directly or indirectly alter the immediate cellular environment, thereby predisposing cells to cancerous change. The information available is so diverse in nature and quality that one of the biggest challenges is to clarify how it should be organized and structured to provide the most straightforward insights into the factors or processes that contribute to etiology in order to determine how best to approach prevention. To be able to deal with the plethora of information and to be able to think through the relations of relevance require that the information be structured appropriately. To achieve this, it is necessary to have a clear framework of understanding and a model of the processes. Any framework or model, if it is to be a useful vehicle for ideas, must embrace or allow consideration of most if not all of the available information. It must also have coherence in terms of each level of organization individually and each in relation to the others.
Cellular processes: life cycle
Cancer is widely recognized as a process in which the genesis of the disorder antedates the clinical presentation of the condition by an extended period of time, which is likely to be tens of years for many of the common cancers (1). The fundamental lesion is damage to DNA, and this damage can be brought about by a range of physical, chemical, or microbiological factors. Because the cell usually has mechanisms to protect itself, sustained damage to DNA must take place against the background of a cellular capability that is inadequate to cope by protecting or effectively repairing the damaged DNA. The capability of a cell to achieve effective prevention or repair depends on the nature of the external cellular microenvironment and the functional capacity of the internal environments (2). The availability of energy, the pattern of macronutrients that act as a potential source of energy, and the availability of an appropriate mix of micronutrients are all critical to these processes. The nutrient environment interacts with hormonal and other signaling processes in maintaining the integrity of the microenvironment and the functional ability of the cell. Smoking, radiation, salted preserved foods, hormones, and obesity can all contribute to damaging DNA. The cumulative cellular damage tips the balance of opportunity for the cell to either repair itself or undergo apoptosis (1). Cells that contain critically damaged DNA but do not undergo apoptosis are potentially neoplastic. Dysregulation of the life cycle of individual cells is, therefore, a fundamental feature of cancer causation.
Population life cycle: time-related changes in infective cancers
The pattern of cancer varies widely from one country to another, broadly matching the level of economic development (1). Thus, for example, in developing countries in Asia and Africa, the most common cancers are those of the mouth and pharynx, larynx, esophagus, stomach, and liver. This contrasts with the pattern seen in economically developed countries in Europe and North America, where cancers of the colon, breast, prostate, and body of the uterus are most common (1). This cross-sectional difference masks the changes that have taken place in time. Cancer of the stomach was much more common in Europe 50 years ago, but there has been a dramatic, progressive decrease by at least 50% since then (3). This suggests strongly that within societies there are patterns of cancer that change in risk for successive cohorts of the population. It is highly suggestive that this cohort effect is a consequence of changes in the environment that expose different age groups to a potentially toxic environment at a particularly sensitive stage of the development of susceptible individuals within the society. This change of patterns can be most graphically illustrated by the changing patterns of cancer experienced by migrant populations, who retain common genetic characteristics while experiencing substantial change in environmental exposure. Thus, the pattern of cancer changes as the children and grandchildren of Japanese migrants to Hawaii become increasingly exposed to the new environment. Cancer of the stomach decreased from 40 to 20 to 12 per 100,000 from the parents’ generation in Japan to the first and then the second generation in Hawaii. By contrast, cancers of the stomach and rectum increased from 4 to 18 by the first generation and cancer of the breast from 11 to 33 to 55 per 100,000 over the 3 generations (4). These dramatic patterns of change within relatively short times indicate very powerful effects of different environments for different risk factors at critical periods during the life cycle, which tend to be cumulative from one generation to the next.
Cancers that are more prevalent in developing countries have broad characteristics in common. Thus, if one uses cancers of the stomach, cervix, or liver as examples, each appears against the background that is broadly characterized as having an inflammatory base associated with a diet of poor quality and, for some exposures, limitations of specific nutrients. Cancer of the stomach is caused by behavioral factors, such as the consumption of salted fish prepared in a particular way that is likely to produce local irritation and inflammation, thereby predisposing to infection with the bacterium Helicobacter pylori, against the background of limited anti-inflammatory and antioxidant protection (1). Changes in behavior, such as a reduction in the consumption of salted fish or wider access to and use of refrigeration, which helps to increase the consumption of fresh fruit and vegetables, together reduce inflammation and enhance antioxidant capability. Cancer of the cervix is caused by the human papilloma virus, but the risk of infection is determined by behavioral considerations and sexual practice; however, there is also a direct interaction with folate status, which is enhanced with the consumption of fresh fruit and vegetables. Thus, a change in sexual behavior and improved diet together help to minimize the risk of developing cancer or the likelihood of the cancer progressing. Cancer of the liver is caused by factors associated with an unclean environment and unhygienic behavior: infection with hepatitis virus or consumption of food contaminated by aflatoxin. Both lead to an inflamed and scarred liver, and this process may be made worse by excessive consumption of alcohol or unregulated absorption of iron. It is not clear for any of these cancers whether poor nutritional status predisposes to infection, thereby establishing the cancer process, or whether infection predisposes to poor nutritional status, thereby enabling progression of the cancer process, or whether other, more complex, patterns of interaction are involved. However, all represent a feature of a potentially hostile environment in which an inflammatory process—whether the consequence of infection, a toxin, or physically damaging exposure in a cellular environment that is nutritionally poor—increases the likelihood that rapidly replicating cells are likely to experience greater DNA damage, which is less likely to be identified and corrected. In intergenerational terms for the population, each cancer rapidly becomes less common when the underlying environmental factors have been improved.
Individual life cycle: linkage of cellular to population life cycle
All cells have a limited range of options open to them: they can divide, undergo apoptosis, or terminally differentiate (2). Neoplastic change is least likely to occur in cells that are terminally differentiated and more likely in rapidly dividing cells or those that fail to undergo appropriate apoptosis. During the cell cycle, critical checkpoints determine the opportunities for progression to one fate or another, and this choice is powerfully influenced by whether the cell is large enough to proceed and whether an appropriate mix of nutrients is available in its immediate environment to allow it to proceed (2). It is clear that cells can be exquisitely sensitive to their nutrient environment, although the detailed character of the preferred environment is less clear. Nevertheless, the composition of the microenvironment can be regulated and controlled to a high degree. This means that mechanisms exist through which the composition of the nutritional environment is sensed, communicated, and regulated. There is some information on how this is achieved for some model systems. One aspect that appears common from one system to another is the critical role played by the monocyte series of cells in sensing and helping to regulate the environment. Thus the macrophage can sense, communicate, and respond to its environment (5) and it is in this context that it carries out immune surveillance and establishes an inflammatory response, promoting a balance of pro- and anti-inflammatory changes, pro- and antioxidant responses, and pro- and antiapoptotic processes (6). This exquisite sensitivity can be either advantageous or deleterious, depending on the specific nature of the context (7).
Cancer represents loss of the ability to sense, regulate, and control the immediate cellular environment. The pattern of nutrients available within this environment might in part be influenced by the dietary intake of nutrients, but homeostatic mechanisms and adaptive processes operate to maintain a degree of constancy, buffering the cellular microenvironment from the usual unevenness of the dietary intake (8). Thus, although the available choices at the cellular level may relate to dietary patterns and hence to the pattern of foods available for consumption from the wider environment, it would be surprising if a strong direct relation could be drawn from one level of organization to another. This makes it extremely difficult to determine the extent to which dietary differences might in practice modulate the cellular microenvironment (9). For progress to be made in our understanding, we need to have a deeper appreciation of the limitations imposed at each of the different levels of organization. There is the need to determine how loss of the ability to regulate and control at the cellular level relates to regulation at the level of the whole body, how this in turn relates to the factors determining patterns of food availability at the group or population level of organization, and how interaction occurs among the different levels of organization. One model that helps to provide a better understanding of the interrelations between genotype and phenotype is that based on cumulated metabolic experience, which embraces the concepts presented by Barker (10,11) in the context of fetal origins of adult disease.
Early life and the origins of adult health and disease
It has been known for many years that nutritional and other environmental exposure during critical periods of early development can markedly affect later size, shape, structure, function, and behavior. However, Barker (10,11) was the first to evince clear evidence that there might also be a direct link between early nutritional exposure and risk of chronic disease, building the evidence that is supportive of a causal relation. Based initially on ecological observations and later on retrospective cohort studies, there is now a considerable body of epidemiological and experimental data that supports the hypothesis. In the earlier observations, the size and shape of the baby at birth was shown to be related to the risk during adult life of ischemic heart disease, hypertension, stroke, type 2 diabetes, obesity, and some cancers (11). These relations were shown to be graded across the usual range of birth weights seen in the population and not a special feature of either a very high or very low birth weight. The observations have been reproduced across a number of populations, and although there may be some debate around details, the general principle appears to apply widely.
Growth and development is a structured process in time and space that is absolutely dependent on an ongoing adequate supply of energy and nutrients that matches the variable need as growth progresses (12). Any limitation in this supply is likely to constrain the pace and pattern of development (13). In functional terms, growth represents a progressive increase in metabolic capacity, and maturity marks the acquisition of the full adult capacity (12). The ability of individuals to adapt and cope with a wide range of environments and environmental stresses reflects a reserve capacity, the magnitude of which might be exposed with a suitable stress test. From maturity there is a gradual loss of capacity, and aging represents the more extreme manifestation of the process. As capacity is lost progressively and the reserve falls, the ability to cope with any form of stress or environmental challenge decreases and eventually becomes manifest as chronic disease. A constraint on growth and development imposed by nutritional limitation at a critical stage of development can have a substantial effect on the acquisition of capacity, particularly if the limitation is of sufficient severity and imposed for sufficient duration during critical stages of organ or tissue development (14).
The nutrient demands vary with the stage of pregnancy and have to be satisfied, regardless of the current dietary intake of the mother. Thus, for a successful pregnancy, the mother draws on nutrient reserves as and when necessary to best satisfy this changing pattern of demands. A woman in a poor nutritional state with limited reserves increasingly depends on her current dietary intake to meet the variable needs of the pregnancy, and this may be considered to be a high-risk strategy. Thus, the mother’s nutritional status at the start of pregnancy best predicts her ability to support the needs of the fetus; the greater her metabolic capacity to deliver nutrients to the fetus, as required, the greater choice for the fetus to meet its needs. Thus, for a well-nourished population of women, the current pattern of food intake does not relate strongly to birth outcomes compared with the nutritional status of the mother at the start of a pregnancy and the capacity to engage in extensive metabolic interchange (15–17). The imposition of any stress is likely to alter nutritional state, either by changing appetite, changing the partitioning of nutrients between tissues, increasing nutrient losses, or altering the pattern of demand for nutrients (15,16). Thus, the stress imposed by infection, the stress imposed by behaviors such as alcohol consumption or cigarette smoking, the stress of metabolic ill health such as diabetes or hypertension, or stresses imposed by deprived social circumstance can all operate to alter the potential availability of nutrients to the fetus and its ability to meet its needs.
Animal studies
The epidemiological evidence on its own is not sufficient to be persuasive of causality. However, evidence obtained from animal studies demonstrates that modest manipulation of the maternal diet before and during pregnancy leads to reproducible change in a wide range of functions and illustrates possible mechanisms through which these intergenerational changes might be achieved (14). These changes are specific but may be widespread across a number of systems of the body, reflecting changed cellular and metabolic function that is reflected in altered glucose tolerance, abnormal appetite control, obesity, immune dysfunction, altered inflammatory responsiveness, and changed behavior.
It has been possible to explore possible mechanisms that underlie these phenomena in different animal species. If, before and during pregnancy, rats are given diets in which the protein content is varied across the normal range of intakes, the pregnancies are carried successfully, and to superficial observation the offspring are well (18). However, more detailed investigation shows that the animals have wide-ranging but subtle changes to the structure and function of many organ systems that are lifelong and eventually lead to metabolic changes representative of disease states. The mechanisms that underlie these profound changes are likely multiple, but profound differences in structure and function can be elicited from a period of altered nutritional exposure as short as the first 4 d of a rat pregnancy (14,19). One important way in which the mother’s nutrient and environmental exposure might alter the delivery of nutrients to the fetus might be through altered structure or function of the placenta. The fetus is normally protected from the effects of glucocorticoids in the maternal circulation through the placental activity of 11ß-hydroxysteroid dehydrogenase. When pregnant dams are offered a diet lower in protein (9%), downregulation of placental 11ß-hydroxysteroid dehydrogenase occurs (20). As a consequence, the fetus is overexposed to maternally derived glucocorticoids, leading to altered development of glucocorticoid-sensitive systems (21). This is reflected in the resetting of hormonal axes, which include the hypothalamo-pituitary-adrenal stress axis, the growth hormone–insulin-like growth factor–insulin axis; the thyroid axis, and the sex steroid axis (14). This resetting leads to altered metabolic responsiveness at later ages, including altered responses to diet and a wide range of stressors. The effect of environmental changes being communicated through successive generations of cells implies epigenetic modification (22). When rats were fed a low-protein diet throughout pregnancy, there was modified expression of the glucocorticoid receptor, peroxisome proliferator-activated receptor-
, and histone acetylase in the liver of the offspring (23). The altered expression was associated with differential methylation of the promoter region of the gene for the glucocorticoid receptor and peroxisome proliferator-activated receptor-. The effect of the low-protein diet was reversed when it was supplemented with folic acid during pregnancy (23). The persistence of the effect of the reduced-protein diet and folic acid supplementation after the end of the dietary intervention shows that maternal diet can program epigenetic mechanisms and hence alter gene expression in the offspring. Epigenetic effects and their modification are recognized as important changes associated with altered risk of neoplastic change (24–26). The fact that programming effects are mediated by similar processes raises the possibility that programmed effects might be directly related to susceptibility to cancer. Programmed differences in metabolic competence carry a range of possible implications in terms of differential risk of cancer because of altered responsiveness to potential toxins or stressors in the environment or changes in immune and inflammatory responses (27).
Metabolic syndrome
Birth weight and the development of metabolic syndrome during later adult life are very strongly associated (10,11,14). This syndrome is characterized by metabolic changes that are associated with an increased risk for chronic disease. The original features of hyperinsulinemia, insulin resistance, dyslipidemia, hypertension, clotting disorders, and obesity now embrace a wider range of features that includes fat patterning. There is an increased risk of cancer associated with an increase in BMI, indicating that obesity is a risk factor for cancer, specifically cancers of the breast, colon, endometrium, and ovary (1). Further, in type 2 diabetes there is an increased prevalence of cancers of the breast, colon, endometrium, pancreas, liver, and prostate (28). This raises the question of whether an increased risk of certain cancers represents another feature of the metabolic syndrome (29), which would suggest that the metabolic disturbance associated with metabolic syndrome creates a cellular microenvironment that predisposes to or promotes genetic instability. If so, one would expect to find an increase in the risk of cancer in those who were born of lower birth weight. The evidence is not strong on this point, but contrary to expectations based on the available evidence, the opposite appears to be true. Thus, for example, in the U.S. Nurses’ Health Study, although there was a strong relation between birth weight and cancer of the breast, the odds ratio for those who weighed <2500 g at birth was 0.55 compared with those who weighed >4000 g at birth, with a graded increase in odds ratio across birth-weight categories (30). Size at birth and adult height are very closely related, and Barker et al. (31) found similar differences in patterns of standardized mortality when comparing populations living in different counties in England. Men and women who were tallest as adults had the lowest mortality from ischemic heart disease and stroke but the highest mortality for cancer of the breast or prostate. Thus, there appears to be a substantial lack of concordance in the data that seek to draw relations among size at birth, risk of metabolic syndrome, and risk of cancer. It is probable that this seeming inconsistency relates to the lack of specificity with which measures of body composition have been used in population studies: in particular, the extent to which BMI has been used uncritically as a proxy for fat mass or adiposity.
Cancer and body composition
The use of BMI has been valuable as a measure of relative weight independent of height and has increasingly been used to mark relative adiposity. When used in this way, assumptions are made about absolute and relative body composition. These assumptions impose limitations on understanding, and the extent to which accepting the assumptions may limit generalizations needs to be carefully considered. For example, compared with UK adults, the average adult from India of similar height, weight, and therefore BMI will have greater fat mass and greater central fat distribution (32), indicative of increased risk of heart disease and metabolic syndrome. These substantial differences in lean and fat patterning are demonstrable at birth and therefore cannot be related simply to aspects of diet or lifestyle during adulthood (33). It has been considered that this difference may be a particular ethnic or genetic characteristic (32,34,35). However, recently we have had the opportunity to look in some detail at the body composition of older men in the United Kingdom whose birth weight was known (36). For a group of men, aged 62–75 y, there were substantial differences in body composition for the same body mass, depending on whether at birth they had higher or lower birth weights within the normal range. Thus for the same height, weight, or BMI, those of lower birth weight had less muscle mass, more fat mass, and more central fat mass. These compositional differences were directly associated with functional measures indicative of an altered or different nutrient cellular microenvironment. Thus, independent of current height, those of smaller size at birth had a phenotype indicative of increased risk of metabolic syndrome.
More detailed characterization of the relation between increased adiposity and risk of cancer in a number of studies suggest that increased central obesity may account for much of the relation for cancers of the breast, colon, endometrium, and ovary (37–49). In a recent study, MacInnis et al. (50) explored the relation between measures of size and shape and colon cancer in men. When divided into quartiles, there was a graded increase in the relative risk for colon cancer in the highest quartile for height, the highest quartile for fat-free mass, and the highest quartile for waist:hip circumference. Height and fat-free mass appeared to be marking similar risk, and when fat-free mass was entered into a multiple regression analysis, height no longer made an independent contribution to risk. By contrast, there was an independent relation between waist:hip circumference and risk of colon cancer that could not be accounted for either by differences in height or differences in fat-free mass. This study demonstrates that height or fat-free mass may have a relation with cancer of the colon that is independent of the relation between waist:hip circumference and cancer of the colon. This suggests that height and waist:hip circumference mark different factors or different aspects of the risk for cancer of the colon. The idea that underlying metabolic differences lead to differential partitioning of macronutrients is an established concept, often articulated as the P-ratio (51). Although the underlying factors that account for these differences are not clear, their importance is being recognized increasingly. The INTERHEART study recorded 15,152 incident cases of myocardial infarction around the world (52). Within each category of BMI, from <20 to >30, there was a graded increase in the odds ratio for myocardial infarction in relation to waist:hip circumference (53). Taken together, these data suggest that height, adiposity, and waist:hip circumference mark different aspects of metabolic regulation and control, and possibly differences in the nutritional microenvironment for cells.
Different anthropometric measures appear to mark different aspects of the effects on phenotype of separate intergenerational experiences at different stages of the life cycle. Although there is certainly a degree of overlap, as a first approximation, general adiposity reflects energy balance directly related to current patterns of activity and dietary experience, for which social drivers are of immediate concern. By contrast, waist circumference is more likely to reflect a statement pertaining to the programming of metabolic regulation, possibly a consequence of epigenetic effects operating during pregnancy or other stages of early life. On the other hand, length or some aspect of fat-free mass represents a longer experience acquired or maintained through generations and, like the secular changes in height, may only be modifiable across generations, reflecting dietary habits over a more extended period of time against the background of social or sexual behavior and requiring a broader change in social opportunities or the removal of stressors for significant modulation.
Obesity and inflammation
It has come to be recognized that the obese state is characterized by a low-grade systemic inflammatory state (54,55). In obese individuals, blood concentrations of inflammatory markers such as C-reactive protein and IL-6 are increased compared with lean individuals, although not to the same degree as in recognized proinflammatory conditions (56). Furthermore, the presence of inflammation has been seen as being causally related to increased risk of cardiovascular disease and type 2 diabetes (57). The etiopathology of the proinflammatory state in obesity needs to be clarified—the nature of the initial trigger to inflammation, the stimulus to macrophage recruitment, and the environment that promotes increased macrophage activity. Importantly, are there specific factors secreted by adipose tissue that promote a microenvironment that predisposes to instability in the genome? If so, are the responses site selective for different adipose depots, which potentially have different lipid compositions, in relation to cancer in different sites (58)? There was a graded increase in the odds ratio (up to 10-fold) for increased circulating C-reactive protein or IL-6 for quartiles of BMI in women, but for waist:hip circumference, the 4- to 7-fold increase in odds ratio was only demonstrable in the upper quartile (56).
For cancers that are common in the developing world, either an infective or toxic exposure generates an inflammatory state that predisposes to genetic instability and increased risk of neoplastic change. The extent to which cancer develops will in part depend on the integrity of either inherent or acquired protective processes that repair or limit any damage that is caused. The evidence now suggests that adiposity and central adiposity themselves promote a proinflammatory environment. The question has to be asked, whether it is the proinflammatory environment that predisposes to genetic instability and increased risk of neoplastic change.
Based on the above analysis, cancer can be considered to be an unusual responsiveness to environmental challenge, and although the specific consequence in terms of genetic damage may depend on the specific nature of the stressor, the extent of the damage may equally be determined by the extent and nature of the response. Regardless of the stressor, there are common aspects to the response to any stressor, be it biological, behavioral, or social in origin. Common aspects of the response include inflammatory and immune responses and activation of the hypothalamo-pituitary-adrenal axis. There will be consequential alterations to appetite, the pattern of nutrient demands, the delivery of nutrients to tissues, and increased nutrient losses. Separately and together, these will lead to a change in the cellular nutrient microenvironment, altered hormonal and cellular signaling, and greater susceptibility to genomic instability.
Nature of cancer; intergenerational effect on phenotype
Ultimately, the cause of cancer has to be a particular constellation of circumstances that come together at particular times to create a cellular microenvironment in which normal cellular regulation can no longer be sustained. This must mean that the usual capacity for the cell to regulate and control its function is exceeded by the stresses imposed on it, because the ability to maintain the relative balance of forces has been surpassed. This imbalance is expressed and made obvious as the inability to regulate normal cell cycling. However, the microenvironment of the cell is itself the product of the integration of metabolic regulation at the level of the whole body. By definition, the achievement of effective regulation presupposes that the body is capable of meeting its own needs, and this is achieved in part from dietary intake but also from the capability of modulating the components of the dietary intake to meet the cellular demands as they vary from one part of the body to another with time. This capability to modulate the nutrients available from the diet to meet the needs of the body is in part a programmed metabolic capability, with the specific phenotype being determined by the nutritional environment experienced by the individual early in life when the opportunity for molding metabolic plasticity still exists. However, the metabolic environment that is offered by the mother for the developing fetus and infant is dominantly influenced by the broader stresses imposed by the society within which she lives and the life choices that are available to her. The balance of opportunities and challenges that individuals and groups face in society is determined by the developmental level that the society has achieved and the options that are available and accessible. As societies develop and progress, this balance changes, and the pattern of change appears cyclical but not necessarily repetitive. For any individual cell, its microenvironment, the stresses imposed, and the capability to withstand these stresses is represented by a summary consideration of the interaction of each level of organization and is likely determined by critical concordance at particular checkpoints in the life cycle of each level of organization.
The question is: How well do we understand the interactions of relevance at each level of organization and to what extent can we characterize the interactions among the different levels of organization and the particular triggers of importance? Reductive science has provided a great deal of information for each level of organization, but we do not yet have a structure or model within which this information can be usefully organized or modeled. In effect, each level of organization represents a black box, but we do not even have stochastic models that enable us to explore interactions within and between levels of organization. Nevertheless, it is clear that simple linear models that have been used in the past to draw associations between phenomena within and between levels are inadequate to the task. The first report from the World Cancer Research Fund and the American Institute for Cancer Research (1) used this approach to good effect but also demonstrated its limitations. The second report in testing this approach to destruction is likely to make it clear that for the future, a different model is required. It is likely that this different model will need to embrace considerations such as organizational theory or game theory applied at the cellular, whole-body, and societal levels; the importance of broader field effects in determining function and behavior, as discussed within the theory of emergentism (59), in terms of the need for organization and the extent to which an organized structure can help to protect cellular integrity and enable normal function; and the ability to synthesize large data sets and identify factors of relevance and importance. Most specifically, because cancer represents a state of disorganization, those mechanisms and systems that enable organization, regulation, and control will be critically important. Achievement of this understanding will require a systems approach applied at the cellular, whole-body, and population levels. Furthermore, determination of the critical interactions among the levels related to the life cycle of each level and the critical determinants in time will be needed.
FOOTNOTES
1 Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 14–15, 2005. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by (in alphabetical order) California Avocado Commission; California Walnut Commission; Campbell Soup Company; The Cranberry Institute; Danisco USA, Inc.; The Hormel Institute; National Fisheries Institute; The Solae Company; and United Soybean Board. Guest editors for this symposium were Vay Liang W. Go, Ritva R. Butrum, and Helen A. Norman. Guest Editor Disclosure: R. R. Butrum and H. Norman are employed by conference sponsor American Institute for Cancer Research; V.L.W. Go, no relationships to disclose. 
2 Author Disclosure: No relationships to disclose.
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