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OCR for page 9
3 Diet arid the Mechanisms
of Carcinogenesis
Much of what we know about the causes of the most common cancers
in humans has been provided by empirical studies of the epidemiology of
cancer, rather than by laboratory studies of mechanisms. For example,
the carcinogenicity of cigarette smoke was established for humans even
though the laboratory investigator had not found a susceptible labora-
tory animal. But our understanding of the mechanisms of carcinogenesis
has come mostly from observations of experimental animal models.
The study of experimentally induced cancers in animals, especially
the production of skin cancer in mice and rabbits, has shown that car-
cinogenesis can be divided into early stages ~ initiation') and later
stages ('promotion ). With rare exception, agents that are powerful
initiators have proved to be powerful mutagens (or to be capable of
being metabolized into mutagens). In contrast, the most powerful
promoters have proved to be agents that alter various cell properties,
especially the structure of the cell surface and the pattern of gene
expression. Despite these studies, the molecular biology of carcino-
genesis remains obscure; it is not known whether~nutagens act as ini-
tiators because they produce mutations or for some other reason, and
the processes underlying promotion remain equally obscure. There
is no unanimity in the scientific community on this point; however,
numerous investigators believe that many, if not most, cancers in
humans will eventually be shown to be the result of our exposure to
the mutagenic initiators and the promoters in our environment.
It is not at all clear that the sequence of steps leading to the
'spontaneous cancers in animals can always be separated into these two
stages. For example, the stages in the production of feline leukemia
and bovine e sophageal cancer certainly do not f it comfortably into that
dichotomy. Similarly, the main risk factor for liver cancer in humans
is chronic infection with hepatitis B virus, even though this virus
does not appear to be a mutagen and there is no evidence that it would
score as positive in any test for ability to promote the later steps of
carcinogene si s.
Therefore, as we try to disentangle the effects of diet on cancer
incidence by hunting through the foods we eat for mutagenic initiators
and for agents that promote the later steps of carcinogenesis, we
should keep in mind that the important dietary determinants of cancer
rates in humans may not fall readily into one of these two classes.
For example, it has not been easy to decide what mechanic so is most
likely to be responsible for the observed effect of a high fat diet on
the incidence of cancer. The following suggestions have been made:
9
OCR for page 10
10 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
o Fat could enhance carcinogenesis by contributing to the forma-
tion of peroxides and other reactive forms of oxygen, which could then
damage DNA.
· A high fat diet may increase excretion of sterol metabolites in
the gut, which in turn may promote tumorigenesis in the colonic epithe-
l ion .
· Certain fatty acids in the diet could be incorporated into cell
membranes, possibly producing changes in cell behavior that are asso-
ciated with promotion.
0 Certain essential fatty acids participate in the synthesis of
prostaglandins, and these may influence twmorigenesis.
· A high fat diet could lead to a change in the level of certain
hormones that in turn might affect the incidence of breast cancer and
some other cancers.
· Lastly, fat may increase cancer rates for reasons that we cannot
at present guess, simply because we do not yet know enough about the
pathways that lead to cancer.
We do not know the extent to which the 'initiator-promoter model
is applicable, but the answer to this question may not be critical to
the design of laboratory experiments or epidemiological studies in the
near future. From the evidence accumulated thus far, however, it seems
clear that carcinogenesis is usually a multistep process. Furthermore,
it has been observed in both epidemiological and laboratory studies
that the effects of diet seem to operate more often upon the later
steps than upon the earlier ones.
Up to this point, we have discussed only those agents that stimulate
the production of cancer. Recent evidence has indicated that there are
other agents that inhibit carcinogenesis. Therefore, as a start to the
further study of the effects of diet, we would like to find out whether
the critical variable is the degree of exposure to agents that stimu-
late the production of cancers (which otherwise would not occur) or to
agents that inhibit the production of cancers (which otherwise would
arise spontaneously). Even though our primary interest is in studying
those agents in our environment that stimulate or inhibit the occurrence
of cancer, we should remember that the action of such agents may often
be modified by familial, possibly genetic, factors. For example, al-
though the incidence of breast cancer is apparently related to fat
intake and age at first pregnancy, it is well known to be strongly ink
fluenced by familial factors, which may have an environmental as well
as a genetic component.
Certain technical advances are now offering us a new source of
information about the mechanisms by which cancers are produced in
OCR for page 11
Diet and the Mechanisms of Carcinogenesis 11
humans. Until recently, the process of looking for signs of DNA damage
or changes in gene composition and expression was like looking for a
needle in a haystack. But new methods may enable us to identify the
fundamental abnormalities that determine the properties of cancer
cells, i.e., which genes are changed, which show altered expression,
and which cellular products are present in an abnormal form or quan-
tity. Thus, we can see that the time may soon come when the molecular
biologist will be able to give the epidemiologist some clues about
factors that are likely to be critical in the production of certain
cancers.
It seems generally true that the benefits derived from fundamental
discoveries about mechanisms tend to arise in completely unexpected
ways. For example, one of the advances that has made the study of
cancer genes possible was the discovery of the restriction enzymes of
bacteria--a result of studies that had no obvious connection with
carcinogenesis. (Because of our knowledge of these enzymes, which
are absolutely specific to certain base sequences and can be used to
break up DNA molecules into short stretches, it has been possible to
work out the exact sequence of whole groups of genes and to determine
exactly the way in which certain cancer cells differ in sequence from
their nonnal counterparts.) Thus, although the following chapters
contain numerous recommendations for specific research areas to be
pursued in the study of diet, nutrition, and cancer, the committee
recognizes that important insights into the mechanisms and dietary
causes of cancer may also come from research in areas that are not
discussed in this report.
RESEARCH RECOMMENDATIONS
This chapter contains no recommendations, because the general mecha-
nisms of carcinogenesis are not within the purview of this report.
Suggestions for research on the mechanists) of action of individual
dietary components are included in the chapters that follow.
Representative terms from entire chapter:
cancer rates
