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Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
1To whom correspondence should be addressed. E-mail: >pg37g@nih.gov" locator-type="email">locator-type="email">pg37g@nih.gov locator="" locator-type="email">
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCreating a new paradigm...Research opportunities for...Integrating new technologyTraining and support for...REFERENCES |
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provided
evidence that one third of cancer deaths are related to diet, it
remains unclear which dietary components may be key in cancer
prevention. Although the complexity of the diet can become
overwhelming, the National Cancer Institute (NCI) of the National
Institutes of Health (NIH) has remained steadfast in its commitment to
defining the roles that diet and nutrition have in the development of
cancer and has provided increased research and training support to
assist in unraveling this interrelationship. Evidence for this
sustained commitment is highlighted by a fourfold increase in NCI
expenditures for nutrition research and training from 1983 to 1998;
this substantial increase reflects a trend that is occurring in some
universities and the private sector. More than one third of the
nutrition-related NCI research is funded by the Division of Cancer
Prevention. Supported investigations cover the gamut from basic
mechanisms of action of dietary constituents, methodology development,
human metabolic studies, clinical trials of dietary modification and
the chemopreventive potential of individual nutrients to
population-based studies.
KEY WORDS: • nutrition • cancer research • paradigm • collaboration • training
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCreating a new paradigm...Research opportunities for...Integrating new technologyTraining and support for...REFERENCES |
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), the true
relationship remains unresolved. Understanding the mechanisms that
accounts for this relationship and the specific constituents that are
responsible for this response will assist in the formulation of
appropriate intervention strategies for target populations when
benefits can be optimized and possible risk determined. Unfortunately,
the current approach to nutrition research may not be adequate to
answer several crucial questions. A new paradigm for nutrition research
that focuses on how essential and nonessential nutrients influence
genetic pathways should not only assist in providing fundamental
threads of information but also achieve an expanded understanding of
the fabric of the relationships that determine risk. |
Creating a new paradigm in nutrition research |
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TOPABSTRACTINTRODUCTIONCreating a new paradigm...Research opportunities for...Integrating new technologyTraining and support for...REFERENCES |
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(Web
site: http://dcp.nci.nih.gov/reports/nutrition/) pointed to the need
for nutrition research to become more interdisciplinary in its approach
to basic cancer biology. To optimize this approach, the group stressed
the need for the current metabolic emphasis to incorporate advances in
molecular biology and genetics. Unquestionably, biochemical and
metabolic studies have paved the road for advances by defining nutrient
kinetics and toxicity, evaluating biomarkers and identifying
intermediate end points. However, the future of nutrition research will
depend in part on the expanded understanding of the interactions
between dietary constituents and individual variability in genetic
profiles (polymorphisms). Although reports in the popular press frequently tout one food or another as the "cure for cancer," nutritional scientists long ago rejected such claims. Even when associations appear strong (e.g., increasing vegetable intake to decrease the risk of breast cancer), proving a cause-and-effect mechanism remains elusive, thus, making dietary recommendations less precise for an individual than for a population. To transcend observational studies into the realm of cause-and-effect relations will likely necessitate a new paradigm in which and explanation of gene–nutrient interrelations becomes of paramount importance.
By taking the example of an association between vegetables and
decreased risk of breast cancer, it is possible to illustrate the
potential of this new paradigm. Epidemiologic studies provide evidence
that societies with a high intake of vegetables have a lower incidence
of breast cancer. Metabolic and experimental studies provide one
possible mechanism for this association by indicating that methylation
of DNA, as can occur in methyl-deficient diets, can increase the
risk of breast cancer through the inactivation of estrogen receptor
gene transcription (Zhu and Williams 1998
).
Methyl-deficient diets can occur from a lack of dietary substances
that influence methylation reactions, such as the folate found in
green, leafy vegetables. However, many individuals with a
higher-than-average intake of vegetables also are diagnosed with breast
cancer; therefore, the association at first glance might appear counter
to the working hypothesis. Consumption of vegetables (or blends) that
have not been shown to be cancer-protective coupled with genetic
variability that increases risks via unrelated mechanisms may account
for this variation in response. By integrating nutrition, molecular
biology and genetics, a clearer picture can emerge regarding
gene–nutrient interactions that are responsible for risk and for
identifications of subgroups of individuals appropriate for dietary
interventions. These fundamental and probing studies will assist in
uncovering the molecular targets responsible for regulating the complex
physiologic events that trigger development, control maintenance of
homeostasis, induce or inhibit cellular proliferation and
differentiation and induce apoptosis. The identification of
polymorphisms that determine an individual’s response to specific
dietary cancer-protective factors, such as folate, or
cancer-inducing dietary carcinogens, such as heterocyclic amines
that arise from high-temperature grilling of meats, will provide
key insights into vulnerable subpopulations. An interdisciplinary
approach holds promise for propelling an understanding of the complex
interactions that occur between dietary constituents and individual
genetic variations. Although this example illustrates what is needed,
in reality, interactions between multiple nutrients and genetic
variations among individuals are far more dynamic. This complexity is
magnified by the fact that cancer is not one disease with one molecular
biology and associated pathway leading to disease development but
actually hundreds of diseases that occur at selected sites—breast
cancer, prostate cancer, colorectal cancer, gastric cancer, lung
cancer, lymphoma and so on. In effect, site-specific cancers have
differing etiologies that likely will require multiple preventive
strategies.
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Research opportunities for dietary prevention |
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). The NCI/DCP is continuing
to encourage collaborative research efforts involving basic research at
the molecular and cellular levels, studies in animal models, human
metabolic experiments and investigations in various population groups,
especially those with higher risks of cancer. Several areas of research
are being considered and encouraged for collaborations to create this
new paradigm for nutrition research. For example, the role of specific
nutrients has gained much attention in research projects in the past
decade. Numerous antioxidants, including vitamins C and E, carotenoids
and flavonoids, as well as calcium, selenium and folate, have been the
focus of studies to determine their ability to reduce oxidative damage
to DNA and other macromolecules caused by free radicals (Lee 1999
). Zinc appears to be protective against carcinogens and
oxidative stress through the activation of transcription factors (e.g.,
MTF 1) that are required for the induction of metallothionein
(Kondo et al. 1999
). Collaborations among basic
nutrition scientists, biologists and molecular geneticists can assist
in explaining the mechanisms by which these dietary constituents affect
the stages in cancer development and progression.
Interactions at the cellular level are exceedingly complex, and nowhere
is it more apparent than in the study of nutrition. Because food is
composed of a vast array of macroconstituents and microconstituents, a
herculean research effort will be required to understand what actually
takes place in an individual exposed to complete diets. Interactions
that occur among dietary constituents, between nutrients and genes and
among environmental and dietary factors demonstrate the complexities
that face nutrition researchers. Innovative research is essential to
create even a basic understanding of these interactions. For example,
"phytochemicals," a term that refers to any compound that
originates from plants, include compounds with anticarcinogenic, as
well as carcinogenic, properties. For example, flavonoids found in
legumes, fruits and berries have been investigated for their
anticarcinogenic properties, as well as being possible candidates for
cancer prevention (Kuo 1997
), yet they also may cause
the translocation of genes, thereby increasing some types of cancer
(Ross 2000
). More than 5000 flavonoids are known to
exist in the diet; to determine the exact benefit, or detriment, of
each flavonoid will likely necessitate creative research methodologies
and multidisciplinary collaborations. The magnitude of the complexity
multiplies when gene–nutrient interactions are considered. Each
individual has a unique genetic makeup, and it is likely that given the
same quantitative exposure to the same dietary factor, each individual
will metabolize the dietary factor differently. To illustrate how
gene–nutrient interactions depend on genetic makeup, the genetically
controlled metabolic pathway of vitamin D includes a vitamin D receptor
in intron 8 (Bsml). Polymorphisms in intron 8
(Bsml) are associated with changes in prostate cancer risk:
a fourfold increase in risk in individuals with one polymorphism and a
60% reduction in risk in individuals with another (Sinha and Caporaso 1999
). Expansion of research collaborations on the
chemical and genetic interactions that occur when food is consumed is
of the utmost importance for future research aimed at optimizing health
while minimizing disease risk.
Another area of research importance is the discovery of validated
biomarkers. Biomarkers, which are chemical or genetic markers that are
used as surrogates to identify risk factors for disease, are being used
in studies of dietary assessment. Biomarkers have advantages in
nutritional studies because they do not rely on recall, can be designed
to measure individual dietary constituents and can be used to monitor
compliance in feeding studies (Riboli et al. 1996
). For
example, tissue and serum levels of n-3 and n-6 phospholipid fatty
acids have been used as biomarkers to reflect dietary intake of fish
(Anderson 1996), and serum levels of ß-carotene
correlate well with the intake of carotenoid-rich vegetables and
fruits (Drewnowski et al.1997
). It is likely that
gene-based validated biomarkers can be developed to identify
individuals at a higher risk of diet-related cancers. The NCI has
developed the Early Detection Research Network (EDRN; Web site:
http://edrn.nci.nih.gov/) (Srivastava and Rossi 1996
) to
identify and validate promising biomarkers for common cancers through
the funding of 18 biomarker developmental laboratories. This
collaborative effort is the type of research strategy needed for the
integration of nutritional sciences with molecular and genetic
sciences.
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Integrating new technology |
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TOPABSTRACTINTRODUCTIONCreating a new paradigm...Research opportunities for...Integrating new technologyTraining and support for...REFERENCES |
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) and seems to be adaptable to
nutrition research. Determining how dietary exposure of untold
combinations of dietary substances simultaneously affects gene
expression and activation can lead to the identification of
polymorphisms that may determine cancer risk. Creating a useable
database of such information would provide a practical method for
screening and identifying individuals with possible risk factors for
various cancers based on genetic or proteomic profiles. Unquestionably,
new technologies, including DNA microarray, as well as imaging
technologies and creative screening techniques, are needed for the new
paradigm in nutrition to be fruitful. |
Training and support for the new paradigm: A call to action |
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TOPABSTRACTINTRODUCTIONCreating a new paradigm...Research opportunities for...Integrating new technologyTraining and support for...REFERENCES |
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Of critical importance to implementation of the new paradigm will be the ability to integrate molecular biology and genetics into training programs for nutrition research. The inclusion of integrated curricula in medical sciences, nutritional sciences and public health programs will provide researchers with the tools to understand and address the complexity of the nutrition–disease interrelationships. Nutrition education programs have been invaluable in creating a focus within the medical and allied health communities on the importance of diet for good health and creating an understanding of metabolic pathways at the cellular level.
In summary, the NCI/DCP is seeking ways to provide funding opportunities for nutrition research to promote the creation of this new nutrition–genetics paradigm. This initiative is intended to foster major interactions and collaborations, to enhance research capabilities and to stimulate nutrition training programs in cancer prevention. The creation of a new paradigm for cancer and nutrition research must come from collaborative efforts among many disciplines. We invite the research community to bring to the NCI/DCP ideas and concepts for redefining how to investigate nutrition in cancer development. Specific opportunities are envisioned for specialized grants in areas of nutrition research that can develop additional capabilities through multidisciplinary collaborations. The new paradigm exists only as an idea—the nutrition community has the opportunity to actualize and implement it.
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FOOTNOTES |
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Manuscript received August 15, 2000. Initial review completed August 22, 2000. Revision accepted August 29, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCreating a new paradigm...Research opportunities for...Integrating new technologyTraining and support for...REFERENCES |
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Drewnowski A., Rock C. L., Henderson S. A., Shore A. B., Fischler C., Galan P., Preziosi P., Hercberg S. Serum beta-carotene and vitamin C as biomarkers of vegetable and fruit intakes in a community-based sample of French adults. Am. J. Clin. Nutr. 1997;65:1796-1802
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Kondo Y., Himeno S., Endo W., Mita M., Suzuki Y., Nemoto K., Akimoto M., Lazo J. S., Imura N. Metallothionein modulates the carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine in mice. Carcinogenesis 1999;20:1625-1627
5. Kuo S. M. Dietary flavonoid and cancer prevention: Evidence and potential mechanism. Crit. Rev. Oncog. 1997;8:47-69[Medline]
6. Lee I.-M. Antioxidant vitamins in the prevention of cancer. Proc. Assoc. Am. Physicians 1999;111:10-15[Medline]
7. National Cancer Institute Nutrition Implementation Group Report of the Nutrition Implementation Group: New Directions for Nutritional Research at the National Cancer Institute 1999 U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute Bethesda, MD.
8. Riboli E., Slimani N., Kaaks R. Identifiability of food components for cancer chemoprevention. Stewart B. W. McGregor D. Kleihues P. eds. Principles of Chemoprevention 1996:23-31 Lyon IARC Scientific Publications.
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Ross J. A. Dietary flavonoids and the MLL gene: A pathway to infant leukemia?. Proc. Natl. Acad. Sci. U. S. A. 2000;97:4411-4413
10. Sinha R., Caporaso N. Diet, genetic susceptibility and human cancer etiology. J. Nutr. 1999;129:556S-559S
11. Srivastava S., Rossi S. C. Early detection research program at the NCI. Int. J. Cancer 1996;69:35-37[Medline]
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