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Opinion

Diet, nutrition and cancer

YOUR DOSE OF MEDICINE - Charles C. Chante MD -
Part II
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, terminally differentiated. Neoplastic change is least likely to occur in cells that terminally differentiated and more likely in rapidly dividing cells or those that fails to undergo appropriate apoptosis. During the cells 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. It is clear that cells can be exquisitely sensitive to their nutrient environment, although the detailed character of 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 system to another is the critical role played by the monocyte series of cells in sensing and helping to regulate the environment. The macrophage can sense, communicate, and respond to environment 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 anti-apoptotic processes. This exquisite sensitivity can be either advantageous or deleterious, depending on the specific nature of the context.

Cancer represents loss of the ability to sense, and control the immediate cellular environment. The pattern of nutrients available within this environment might be 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. 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. 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 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 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 casual 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. 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. Any limitation in this supply is likely to constrain the pace and pattern of development. In functional terms, growth represents a progressive increase in metabolic capacity, and maturity marks the acquisition of the full adult capacity. 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.

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, 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. 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. 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. 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. 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 life long 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 day of a rat pregnancy. 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 11B-hydroxyseroid dehydrogenase.

When pregnant dams are offered a diet lower in protein (9 percent), downregulation of placental 11B-hydroxyseroid dehydrogenase occurs. As a consequence, the fetus is overexposed to maternally derived glucocorticoids, leading to altered development of glucocorticoid-sensitive systems. This is reflected in the resetting of hormonal axes, which include the hypothalmus-pituitary-adrenal stress axis, the growth hormone-insulin-like growth factor-insulin axis; the thyroid axis, and the sex steroid axis. 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. When rats are fed a low-protein diet throughout pregnancy, there was modified expression of the glucocorticoid receptor, peroxisome proliferators-activated receptor-, and histone acetylase in the liver of the offspring. The altered expression was associated with differential methylation of the promoter region of the gene from the glucocorticoid receptor and peroxisome proliferators-activated receptor-.

The effect of the low-protein diet was reverse when it was supplemented with folic acid during pregnancy. The persistence of the effect of the reduced-protein diet and folic acid supplementation after the end of the dietary intervention show 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. The fact that programming effect is mediated by similar processes raises the possibility that programmed effect 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.

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ALTERED

CHANGES

ENVIRONMENT

METABOLIC

NUTRIENTS

NUTRITIONAL

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