Affiliations of author: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA.
Correspondence to: Edward Giovannucci, M.D., Sc.D., Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: edward.giovannucci{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Until recently, the health aspects of tomatoes had received relatively little attention. The antioxidant properties of lycopene, a carotenoid consumed largely from tomatoes, have raised interest in the tomato as a food with potential anticancer properties (8). Higher consumption of tomatoes is in fact compatible with current general recommendations aimed at increasing intake of fruits and vegetables. Nonetheless, whether unique benefits derive from tomatoes is important to establish because tomatoes are used in many processed items that are not necessarily identified with fruit or vegetable consumption. These items include tomato and spaghetti sauce, tomato soup, salsa, ketchup, and tomato paste. Moreover, many of these processed foods are better sources of bioavailable lycopene than are fresh tomatoes (9-11).
This review examines the epidemiologic evidence regarding consumption of tomato and related products with the risk of cancer at various body sites. The main purposes of this review are to assess the evidence for benefits by specific cancer site and to consider the strengths and limitations of the studies that help indicate whether observed associations are causal. Criteria considered include the strength of any associations, consistency of results by study design (case-control or cohort), method of exposure assessment (questionnaire or biomarker), the factors controlled for by matching or through data analysis, and the potential for residual or uncontrolled confounding. The potentially beneficial constituents of tomatoes and the implications for current dietary recommendations are then discussed.
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REVIEW OF EPIDEMIOLOGIC STUDIES |
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TOTAL CANCER |
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LUNG AND PLEURAL CANCERS |
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Although the focus has been on ß-carotene, the literature shows
that several fruit and vegetable groups, including leafy green and
yellow/orange vegetables, are associated with a lower risk of lung
cancer (3). Fourteen studies (16-29) have reported
specifically on tomato or lycopene consumption in relation to lung
cancer risk; of these, 10 (17,18,20-24,26-28) suggest either
a statistically significant or a suggestive inverse association (Table
1). These studies, mostly case-control in design, generally adjusted
for smoking history, the most important potential confounder for lung
cancer. An additional study (30) indicated that higher
prediagnostic dietary intake of tomatoes (recalled after diagnosis)
among lung cancer case subjects was associated with better survival
from lung cancer (Table 1).
One study (22)
found an inverse association between tomato intake and squamous cell
and small-cell lung cancer but not with other histologic types.
Statistically significant associations were observed in multiple U.S.
populations, China, and Spain, and non-statistically significant
inverse associations were noted in the U.K., Norway, and Finland.
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Only one study that reported on mesothelioma (cancer of the pleura or peritoneum) was identified (31). Overall, a 40% reduction in risk was noted for those consuming tomato or tomato juice 16 or more times a month versus nonconsumers. Only 1.7% of control subjects reported not consuming tomatoes or tomato juice as opposed to 9% of case subjects, suggesting nonconsumers of tomato products to be at relatively high risk for mesothelioma.
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STOMACH CANCER |
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COLORECTAL CANCER |
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ORAL/LARYNGEAL/PHARYNGEAL CANCER |
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ESOPHAGEAL CANCER |
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PANCREATIC CANCER |
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PROSTATE CANCER |
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Three studies (69-71) have examined serum carotenoids using prediagnostic samples in relation to prostate cancer risk. The first study (69), which was based on serum obtained in 1974 from 25 802 persons in Washington County, MD, found a 6.2% lower median lycopene level in prostate cancer case subjects diagnosed during 13 years compared with age- and race-matched control subjects. The estimated RR was 0.50 (95% CI = 0.20-1.29) between high and low quartiles of lycopene. No other carotenoid was associated with prostate cancer risk. Preliminary results from the Physicians' Health Study (70), which was based on 581 case subjects, found a statistically significant RR of 0.56 (95% CI = 0.34-0.91) when comparing high quintile with low quintile of plasma lycopene.
A serum-based study conducted during the period from 1971 through 1993 in a Japanese-American population in Hawaii (71) did not detect any association between serum lycopene levels and risk of prostate cancer. However, several characteristics of the study may have contributed to the lack of an association, including use of a single assessment of serum lycopene to characterize follow-up for up to a 22-year period (only 14 cases occurred within the first 5 years of follow-up), inclusion of "low virulence" disease (28% were diagnosed incidentally during surgery for benign prostatic hyperplasia), and very low serum lycopene levels [the median serum concentration among control subjects was only 134 ng/mL, compared with 320 ng/mL in the study by Hsing et al. (69) and 424 ng/mL in the sample of 121 health professionals (64)]. Ethnic differences in prostate cancer etiology may also be important, inasmuch as men of Asian descent may have an inherently low susceptibility to prostate cancer.
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BLADDER CANCER |
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BREAST CANCER |
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CERVICAL CANCER AND PRECURSORS |
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OVARIAN CANCER |
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SUMMARY OF EPIDEMIOLOGIC EVIDENCE |
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Including studies that have reported results but did not specify RRs, 72 studies have reported on intake of tomatoes, tomato-based products, and lycopene or blood or tissue level of lycopene and risk of a cancer site. These were based on 66 reports, some of which separately analyzed various cancer sites (e.g., colon and rectum). Of these 72 studies, 57 found inverse associations between tomato or lycopene consumption or blood lycopene level and risk of cancer; 35 of these inverse associations were statistically significant. The remaining 15 studies were inconclusive or indicated a slight direct association, with RRs mostly within the range between 1.0 and 1.2. No statistically significant direct association between tomato or lycopene consumption and risk for any cancer site was noted.
Table 6 shows the RRs from 61 studies that provide
data; there are 74 RRs because some studies present results stratified
by sex, racial or ethnic group, colon and rectum cancers separately,
and results both for blood lycopene level and for dietary tomato or
lycopene intakes. Almost half the studies found RRs around 0.6 or less,
about two thirds with RRs less than 0.8. The results did not vary
appreciably whether they were based on prospective or retrospective
data or whether they were based on dietary intakes or blood lycopene
levels. The RRs (two-sided P values) for biomarker-based
studies are 0.16 (P<.02), 0.26 (P = .004), 0.32
(P<.05), 0.37 (P = .01), 0.4 (P = .08),
0.5 (P = .02), 0.5 (P = .06), 0.50 (P =
.26), 0.56 (P = .05), 0.62 (not significant), 1.01
(P = .97), 1.0 (not significant), 1.1 (P = .86),
1.14 (P = .69), and 1.36 (P = .59). Of these 15
studies, 10 had RRs less than or equal to 0.62, and eight were
statistically significant or of borderline statistical significance
(P
.08), and in five of the studies
(59,69,70,75,91), an inverse relationship was limited to
lycopene among carotenoids.
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RR estimates for the various cancers are shown in Fig.
1. The tendency for an inverse association between
consumption of tomatoes or tomato products or lycopene levels is
observed for a variety of cancer sites. The data are most compelling
for cancers of the prostate gland, lung, and stomach. Data are also
suggestive for several other cancers, including pancreatic, colorectal,
esophageal, oral, breast, and cervical cancers. Data regarding the
relationship between tomato consumption or lycopene level and cancer risk for
other cancer sites are too limited at present to support firm conclusions.
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Potential for Bias and Confounding as Explaining the Results
Biases occur when, through faulty data-collection techniques, the associations in the study population are distorted. For example, in some case-control studies, for which the disease status is known at the time of interview, case subjects may recall past diet differently from control subjects. Biases possibly may have occurred in specific settings, but that a single, strong methodologic bias accounts for all these findings is not plausible. Recall biases, for instance, cannot account for associations observed in prospective studies, particularly those based on blood levels of lycopene rather than on dietary recall.
Publication bias (e.g., results reported in the literature only from studies that found a relationship) is unlikely to be of major importance for our overall findings because, if no underlying association existed, one would expect as many direct associations as inverse associations to be reported. Here, 35 statistically significant inverse associations were identified, but none with direct associations were found. However, for specific cancer sites for which only a small number of reports have been published, selective publication may be a potential factor.
Although systematic errors or bias in reporting tomato or lycopene intake cannot account for all the findings, it is possible that the association between high tomato consumption and lower risk for numerous cancers is not causal but rather is secondary to some confounding factor(s) associated with tomato intake. This possibility cannot be ruled out entirely, but it is unlikely for several reasons. For confounding to occur, the confounding factor has to be simultaneously an important risk or protective factor for that cancer and correlated substantially with tomato intake. As shown in the tables, known or suspected risk factors were controlled for in many of the studies. In general, confounding from the considered factors did not account for the observed relationships.
It is possible that some unidentified confounding factor accounted for these associations. However, given the variety of cancers studied, the different etiologies for cancers, and the diversity of populations studies, uncontrolled confounding is unlikely to account for most of the inverse associations with tomatoes or lycopene. The pattern of potentially confounding factors for tomato products will likely vary among cancers, which have different risk factors. Moreover, dietary patterns differ among countries, and at least one statistically significant inverse association for tomato products was observed in 10 countries (United States, Italy, Holland, Spain, Sweden, Poland, Australia, Iran, China, and Japan). The pattern of covariates will also likely vary by type of tomato product. For example, in the Health Professionals Follow-up Study (64), fresh tomatoes tended to be associated with "healthy" lifestyle practices, tomato sauce displayed no discernible pattern, and pizza was associated slightly with "unhealthy" practices, yet all three items were inversely associated with risk of prostate cancer.
The inverse association between plasma lycopene level and cancers of
the prostate, lung, cervix, breast, and pancreas is particularly
interesting because plasma and tissue lycopene levels are poorly
correlated with overall vegetable and fruit intake because of the
diverse nature of tomato products [r = .11 (93); r
=
.11 in women and .16 in men (94)]. Unlike lycopene levels,
most other carotenoid levels correlate reasonably well with vegetable
and fruit intake (93,94). Furthermore, in a study of a general
U.S. population, lower serum concentrations of ß-carotene,
-carotene, lutein, and ß-cryptoxanthin were generally
associated with male sex, higher alcohol intake, increased smoking, and
higher body mass index; dietary and serum lycopene levels were not
associated with these factors (95). Thus, it is unlikely that
the inverse association between plasma lycopene level and risk of
various cancers is a result of lycopene's being a nonspecific marker
of fruit and vegetable intake or related "healthy" behaviors.
Dose-Response Relationship
Although most studies indicate an anticancer benefit of tomato consumption, it is difficult to draw firm conclusions regarding the dose-response relationship. For the most part, RRs appeared to decrease proportionally to increasing intake of tomatoes or related products. Within the observable range, there was no firm evidence of an intake level where the trend toward decreasing risk begins to reverse, although few data are available regarding intakes of tomatoes or tomato-based products exceeding one serving per day. Caution is advisable regarding pharmacologic doses of lycopene because all of the epidemiologic data are based on typical dietary intakes. Moreover, one animal study of lung cancer (96) suggests a benefit of lycopene intake at lower levels but possibly an adverse effect of lycopene intake at very high levels. Benefits may also vary by the specific type of tomato products because processing and cooking may influence the level or bioavailability of the bioactive compounds (e.g., lycopene).
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POTENTIALLY BENEFICIAL ASPECTS OF TOMATOES AND TOMATO-BASED PRODUCTS |
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In addition to being a substantial source of some traditional
nutrients, tomatoes are rich in several phytochemicals believed to have
anticancer properties. Among the most prominent phytochemicals in
tomatoes are the carotenoids, important pigments found in plants, and
photosynthetic bacteria, fungi, and algae. These organisms synthesize
phytoene, a 40-carbon molecule with 9 double bonds (in the
trans configuration), which serves as a precursor for more
than 600 carotenoids. A series of desaturation steps leads sequentially
to phytofluene, -carotene, neurosporene, and lycopene, a
symmetrical, acyclic 40-carbon molecule with 13 double bonds (11
conjugated). Enzymatic cyclization of the end groups of lycopene
results in
-carotene (one ß-ionone ring) and ß-carotene
(two ß-ionone rings). The ß-ionone rings are critical for
vitamin A activity; other ring structures formed are devoid of vitamin
A activity. Thus, cleavage of
-carotene forms one vitamin A
molecule, while cleavage of ß-carotene leads to two vitamin A
molecules. Oxygenation of the ß-ionone rings leads to the more
polar oxycarotenoids or xanthophils, such as ß-cryptoxanthin (one
oxygenated ring, half the provitamin A activity of ß-carotene) and
lutein (two oxygenated rings and hence no provitamin A activity).
Plants vary substantially in their overall production of carotenoids
and in the activities of various enzymes involved in desaturation,
cyclization, and oxygenation to produce a wide range of carotenoids.
For example, the red color of tomatoes results from lycopene,
suggesting that red tomatoes have insufficient cyclase activity to
convert lycopene to -carotene and ß-carotene efficiently.
Variation in different strains of tomatoes exists, as evidenced by
yellow tomatoes, which are relatively low in lycopene. Among foods
typically consumed by humans, tomatoes are a particularly rich source
of several carotenoids. Of 14 carotenoids found in human serum, tomato
and tomato-based products contribute to nine and are the predominant
source of about half of the carotenoids (99). Tomatoes are low
in ß-carotene (most of the provitamin A activity from tomatoes is
from
-carotene) and low in the polar xanthophils, but they are by
far the major source of the remaining nonpolar carotenoids.
Overall, tomatoes are an important source of several nutrients and a predominant source of several carotenoids, particularly lycopene. Very few items other than tomato products contribute to dietary lycopene; these include watermelon, pink grapefruit, and apricots. Tomatoes are also a source of other potentially beneficial phytochemicals, including phenylpropanoids (phenolic acids), phytosterols, and flavonoids (97). However, the biologic relevance of these latter compounds, plus the relative importance of tomatoes as a dietary source of these, is unknown.
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BIOLOGIC PLAUSIBILITY OF AN ANTICANCER EFFECT OF LYCOPENE |
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The unique biochemical properties of lycopene may render it able to protect cellular components against specific types of damage from highly reactive oxygen species. The source of the reactive compounds differs by tissue type and includes smoking, sunlight, chronic inflammation, and normal metabolic processes (110-112). For example, smokers' lungs are exposed to high levels of nitric oxide (NO), which can react with oxygen to produce the NO2· radical. NO2 radicals survive for long enough in fresh smoke to reach lung tissue (113). Lycopene is one of the major carotenoids found in lung tissue, and concentrations vary widely among individuals (114). Using an in vitro assay, Böhm et al. (115) showed that carotenoids are effective in protecting lymphocytes from NO2 radical damage and that lycopene was at least twice as effective as ß-carotene. Lycopene was shown to possess anticancer properties in a mouse lung carcinogenesis model (96).
Chronic infection by Helicobacter pylori is a major established risk factor for gastric cancer. Chronic infections may increase cancer risk by increasing the oxidative load (116). Elevated DNA oxidation occurs early during H. pylori infection (117). Dietary antioxidants, including lycopene, may potentially reduce the impact of oxidative load from H. pylori infections in the stomach. Another potential contributing factor to stomach cancer is the endogenous formation of N-nitrosamines. Vitamin C has been considered to be an inhibitor of the nitrosation that generates N-nitrosamines. It is interesting that an ecologic study in Japan (45), an area with a high incidence of stomach cancer, showed no association between average plasma vitamin C level and stomach cancer, and, in fact, the area with the lowest gastric cancer incidence had the lowest vitamin C level. In contrast, plasma lycopene level was associated with stomach cancer rate more so than the levels of other "antioxidant" nutrients assessed (vitamins A, C, and E and ß-carotene) (45). A study of determinants of endogenous generation of N-nitrosamine in rats (118) suggested that various aspects of food products may explain their inhibitory effect, including pH, and ascorbic acid, lycopene, and ß-carotene contents. Tomato and tomato-based products are the predominant sources of lycopene and one of the major sources of ascorbic acid in some populations.
Reactive oxygen compounds may contribute to prostate carcinogenesis (119,120). Prostate epithelial cells in many men at the age of risk for prostate cancer are likely to be exposed to inflammatory-related reactive oxygen species because of the high prevalence of prostatitis. However, whether an antioxidant property accounts for the apparent benefit of tomato product consumption on prostate cancer risk remains unproven.
If oxidation proves critical to carcinogenesis, the dietary
contribution to antioxidation is likely to be immensely complex.
Synergy among antioxidants exists in experimental systems
(121), and synergistic effects are likely to be more complex
in vivo. For example, synergy between -tocopherol and
ascorbic acid is well established (121), resulting from the
ability of ascorbic acid to reduce
-tocopheroxyl radicals, thereby
recycling
-tocopherol. Complex synergistic effects may occur as a
result of such direct interactions (e.g., recycling), different
abilities of antioxidants to scavenge the various reactive oxygen
species thus enhancing overall protection (103), and the
localization of different antioxidants in diverse subcellular
compartments. Possibly, the benefits of tomatoes may result from the
complex interaction of various carotenoids, ascorbic acid, and other
antioxidant polyphenolic compounds.
Although the notion that lycopene may exert its role in humans through limiting cellular macromolecule damage from reactive oxygen species is appealing, other mechanisms may be operative. In addition, preliminary in vitro evidence indicates that lycopene reduces cellular proliferation of various cancer cell lines induced by insulin-like growth factor-I (IGF-I) (85). This finding, which requires confirmation, is intriguing, given recent evidence that the circulating level of IGF-I is positively associated with higher risk of various cancers, including prostate cancer (122). Various other potential mechanisms have been postulated (100,108,123,124). Most of the mechanistic data have been based on in vitro studies, but a recent study (125) found that supplementation with tomato products, as well as carrot and spinach products, resulted in a marked decrease in endogenous levels of strand breaks in lymphocyte DNA. More human studies are clearly needed.
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CONCLUSIONS |
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The benefits of tomatoes and tomato products are often attributed to the carotenoid lycopene. However, a direct benefit of lycopene has not been proven, and other compounds in tomatoes alone or interacting with lycopene may be important. It is critical to recognize that the current evidence regarding dietary intake and lycopene blood concentrations reflects consumption of tomatoes and tomato products rather than purified lycopene supplements. The pharmacokinetic properties of lycopene remain poorly understood, and it is premature to recommend use of pharmacologic doses of lycopene for any health benefit. Further research on the bioavailability, pharmacology, and biology of this potentially important carotenoid is clearly warranted. Until more definitive data regarding specific benefits of purified forms of lycopene are available, current recommendations should emphasize the health benefits of diets rich in a variety of fruits and vegetables, including tomatoes and tomato-based products.
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NOTES |
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I thank Kathleen Markham for her outstanding technical support.
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Manuscript received July 24, 1998; revised November 5, 1998; accepted December 30, 1998.
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