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Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Brady Urological Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205
2To whom correspondence should be addressed. E-mail: eplatz{at}jhsph.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONOverview of energy restriction...Evidence that energy imbalance...Future directionsLITERATURE CITED |
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KEY WORDS: • prostate cancer • energy intake • risk
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONOverview of energy restriction...Evidence that energy imbalance...Future directionsLITERATURE CITED |
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), and its incidence is increasing around the world. Despite decades of epidemiologic investigations, only three factors are known with certainty to be associated with an increased risk of prostate cancer older age, being black and positive family history—and all three are factors that men cannot control (2
). Leads for modifiable risk factors have emerged from the literature when study design, choice of population, quality of exposure, and outcome assessment and number of cases are taken into account. For all stages of prostate cancer, low intake of selenium (3
) and the antioxidant lycopene (4
) appear be associated with a higher risk. Suspected modifiable risk factors for advanced stage prostate cancer, especially for distant metastases, and death from prostate cancer include high intake of red meat or saturated fat, dairy products and calcium; low vigorous physical activity; cigarette smoking (2
); and possibly higher central adiposity (5
). That many of the suspected risk factors are associated with more advanced disease but not with early disease suggests that these risk factors may act on progression rather than on initiation or promotion. Some of these suspected prostate cancer risk factors—high red meat or saturated fat intake, low vigorous physical activity and larger body size—are correlated with energy intake. These observations lead to the question, Does excessive intake of energy relative to energy expenditure adversely affect risk of clinically important prostate cancer?
Energy demand is determined primarily by basal metabolic rate but also by activity level and body size (6
). Activity level, including fidgeting, and body size, primarily lean body mass, are the major contributors to interindividual variability in energy demand (6
,7
). When an individual consumes more energy than is needed for maintenance of body size, that individual is said to be in energy imbalance. The effect of energy imbalance, as indicated by obesity, on the incidence of and death from heart disease and cancer is well supported (8
–12
).
Evidence that excess energy intake relative to energy demand is a risk factor for prostate cancer is presented here. Also discussed are directions for future research needed to uncover the biological mechanisms underlying the adverse effects of energy imbalance, where in the natural history of prostate carcinogenesis energy imbalance plays a role and the optimal balance between energy intake and demand.
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Overview of energy restriction in models of carcinogenesis |
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TOPABSTRACTINTRODUCTIONOverview of energy restriction...Evidence that energy imbalance...Future directionsLITERATURE CITED |
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,14
). Compared with animals given free access to food, animals fed energy-restricted diets are smaller; have reduced fat mass, lower body temperature, enhanced insulin sensitivity and fewer mutations; and live longer. These effects are generally proportional to the extent of energy restriction (14
). For example, in a study of mutagen-initiated mammary carcinogenesis, energy restriction of 10, 20 and 40% resulted in a reduction in the mean number of tumors per animal expressed as a the percentage of the control group of 63, 48 and 17%, respectively (15
). Mediators of the adverse effects of energy imbalance on carcinogenesis.
Energy restriction influences a broad spectrum of cellular and tissue activities, and many of its effects plausibly could ameliorate carcinogenesis. Two of the effects of energy restriction—enhancement of apoptosis relative to proliferation and antiangiogenesis—are hypothesized to attenuate the promotion and progression phases of carcinogenesis. These effects are highlighted here to set the stage for the prostate-specific findings that are described later.
Tumor development is thought to be due in part to an imbalance between cell growth and cell death (16
). In tumors the rates of both proliferation and apoptosis are higher than those in normal tissues (14
,17
). However, tumors grow because the rate of proliferation outpaces the rate of apoptosis. The inhibition of cellular proliferation by energy restriction may be due to impedance of progression through the cell cycle. One study showed that energy restriction leads to substantially higher production of cyclin-dependent kinase inhibitor p27, decreased production of cyclin D1 and a shift to the G0/G1 phases of the cell cycle (14
).
Perhaps equally if not more important is the enhancement of apoptosis by energy restriction. Apoptosis proceeds through two major pathways: direct signaling by death peptides such as FasL or tumor necrosis factor through cell surface receptors or indirect signaling triggered by loss of focal adhesion, inability to repair damaged DNA or other mechanisms (18
,19
). Both pathways culminate in activation of caspases, which are proteases that are the direct effectors of cell death. Hallmarks of apoptosis are DNA fragmentation, cell cytoskeleton destruction and membrane blebbing (18
). Numerous studies have demonstrated enhanced apoptosis with energy restriction. For example, moderate energy restriction (20–25% of unlimited feeding) after mutagen-initiation and partial hepatectomy in rats resulted in a 12-fold increase in the proportion of apoptotic cells in the liver (17
). In that study, the number of rats with hepatocellular carcinoma and the number of hepatocellular carcinomas per rat decreased. However, tumor size and the number of preneoplastic foci did not change. In another study of mutagen-initiated mammary gland carcinogenesis in rats, apoptosis was enhanced in both premalignant and malignant lesions (20
). The extension of ducts, which consisted of the cells at risk for mammary tumors, was reduced proportionally to the reduction in body size, but ductal branching, tumor volume and breast density were reduced more than body size. The degree of lesion inhibition increased as the histological severity increased—from 36% for intraductal proliferation, to 65% for ductal carcinoma in situ, to 95% for adenocarcinoma—with energy restriction of 40% (20
). Another study from the same group observed that the incidence of preneoplastic mammary lesions increased with increasing energy restriction, whereas the number of adenocarcinomas decreased (15
). Taken together, these studies support the observation that energy restriction augments apoptosis. They also indicate that the greatest benefit of energy restriction is later in the natural history of tumorigenesis, possibly influencing the transition from preneoplastic lesions to patent adenocarcinoma, which in some cases may result in an accumulation of preneoplastic lesions.
The shifting balance from greater proliferation toward greater apoptosis with energy restriction may also explain the observed reduction in mutations in energy-restricted animals. Cells with DNA damage may be more likely to be lost through programmed cell death, leaving behind a pool of unaffected cells. Alternatively, reduced proliferation in energy restriction limits the likelihood that DNA damage will become fixed as mutations in progeny cells (21
).
Continued tumor growth and the ability to metastasize require the formation of new blood vessels to maintain cellular access to oxygen (22
). For an in-depth review of the role of angiogenesis and cancer, see Carmeliet and Jain (23
). Hypoxia occurs in cells located >100–200 µm away from a blood vessel (23
). Hypoxia is one of several switches that up-regulates the production of hypoxia-inducible factor-1, which in turn up-regulates angiogenesis factors, such as vascular endothelial growth factor (VEGF)4
(24
). Newly formed blood vessels in tumors are structurally abnormal, are leaky and do not form a pattern that will produce adequate perfusion. The resultant hypoxia despite the presence of microvessels may select for tumor cells that no longer undergo apoptosis when hypoxic, thus rendering them more aggressive (23
). In addition to allowing for the continued growth of a tumor, the formation of new vessels may be a conduit for the travel of cancer cells to new sites, forming metastases (23
).
Insulin-like growth factor (IGF)-I as a shared mediator of the adverse effects of energy imbalance on carcinogenesis.
The specific mechanisms underlying how energy imbalance may adversely affect the balance of proliferation with apoptosis and enhance angiogenesis remain to be resolved. Hints point to one of several possible shared mediators: IGF-I. Because detailed reviews are available describing the activities of IGF-I (25
,26
), it is described here only briefly. IGF-I is a peptide growth factor produced by the liver that shares homology with insulin (26
). IGF-I is responsible for regulating fetal growth and, with growth hormone, influences body size and composition. Through the type I IGF receptor, IGF-I promotes proliferation and inhibits apoptosis (25
). IGF-I receptor signaling activates the Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol-3'kinase pathways (18
,25
). These pathways phosphorylate pp90RSK and pp70S6K, respectively, which in turn inactivate nuclear receptors by phosphorylation. When unphosphorylated, these receptors likely mediate the growth-promoting effects of growth factors by transactivating transcription of antiapoptotic factors.
IGF-I is implicated indirectly as a mediator of the adverse effects of energy imbalance. In mouse models predisposed to tumor formation because of p53 loss, energy restriction both early and later in life yields reduced plasma IGF-I levels and a delay in onset of tumors (21
,27
). Direct evidence that IGF-I mediates the adverse effects of high energy intake comes from a study of mutagen-initiated bladder cancer comparing mice freely fed, fed an energy-restricted diet or fed an energy-restricted diet with IGF-I supplementation. This study showed that the benefit of energy restriction on number of affected animals and number of tumors per animal is lost if IGF-I is supplemented back to normal levels (28
). IGF-I supplementation also led to larger tumor volume and poorer histology, indicating that IGF-I contributes to tumor progression (29
).
In addition to its endocrine activities, IGF-I acts as a paracrine growth regulator, including action in the prostate where it is produced by the stroma (30
). Epithelial cells in prostate tumors also may produce IGF-I (31
). Higher circulating concentrations of IGF-1 have been associated with several common cancers (32
), including prostate cancer (33
). Despite the evidence that IGF-1 may in part mediate the adverse effects of energy imbalance, in cross-sectional studies in adults, plasma IGF-1 concentration is not clearly correlated with energy intake, obesity or physical inactivity (34
). However, fasting does reduce plasma IGF-1 concentrations in adults (35
,36
), possibly suggesting that in the cross-sectional studies the range of exposures may not have been adequately extreme for detecting the correlation.
Other mediators of the adverse effects of energy imbalance on carcinogenesis.
Other hypotheses have been advanced, particularly by Kritchevsky (13
), to explain the adverse effect of energy imbalance on carcinogenesis. Insulin is a growth factor and experimental insulin deprivation results in inhibition of tumor growth. Thus the effects of energy restriction on insulin levels (decrease) and insulin receptor numbers (increase) may contribute to decreased tumor burden (13
). The activity of antioxidant enzymes is increased with energy restriction, conferring greater protection against mutagenic reactive oxygen species (13
). Protein oxidative damage is reduced with energy restriction (37
). Energy restriction is also associated with higher levels of glucocorticoid hormones (13
,15
). Elevations in glucocorticoid hormones may enhance a stress-responsive shift in an array of factors that protect against carcinogenesis (38
), including modulating cell cycle control (14
). The reduction in glycemia and hypertriglyceridemia from energy restriction limits the energy supply to cells and thus may limit the ability of the cells to grow into tumors (39
).
Relevance of energy restriction in mouse and rat models to energy imbalance in humans.
Inferences made about the benefits of energy restriction on carcinogenesis are likely very relevant to understanding the adverse effects on carcinogenesis of excessive energy intake relative to expenditure. The energy restriction in the animal models described earlier is not at starvation level. Free access to food in combination with the lack of physical activity of caged experimental animals (40
,41
) renders them not unlike people living in Western cultures. The typical level of restriction, 20–40% of free-access intake, has been theorized to be compatible with the underlying energy requirements of these animals (42
; D. M. Klurfeld, Department of Nutrition and Food Sciences, Wayne State University, Detroit, MI, personal communication). Thus the findings of reduced tumor burden with energy restriction compared with free-access feeding is not a peculiarity of underfeeding but instead implies that overeating increases tumorigenesis (41
). Unlike in human studies, in animal experiments energy balance does not need to be considered. These animals have relatively homogeneous body weight because of shared genetic backgrounds and are equally inactive because of caging.
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Evidence that energy imbalance influences prostate carcinogenesis |
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TOPABSTRACTINTRODUCTIONOverview of energy restriction...Evidence that energy imbalance...Future directionsLITERATURE CITED |
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Migrant studies.
When adult men move from countries with low prostate cancer incidence and mortality rates, such as Japan, to the counties with substantially higher rates, such as the United States, their risk of prostate cancer increases (43
). When individuals immigrate, they may change many aspects of their lives, possibly including the balance between the amount of food consumed and its energy density relative to the amount of physical activity. Unlike for stomach cancer, where rates for immigrants from high-risk countries remain substantially higher than their adopted lower risk homeland (43
), the increase in prostate cancer risk is more rapidly acquired. This observation suggests that the factors that the immigrants change with acclimatization are those that act later in the natural history of prostate cancer. Thus indirectly, migrant studies show that energy imbalance may be a possible contributor in prostate cancer risk.
Ecological studies.
In ecological studies (also known as correlation studies), disease rates for several countries or regions are plotted against per capita exposure. Three such studies (44
–46
), which used country-specific supply data supplied by the United Nations to estimate per capita energy intake, show a positive correlation between per capita energy intake and prostate cancer incidence or mortality (Table 1
). In the study by Armstrong and Doll (44
), the correlation coefficients were 0.3 (23 countries) and 0.6 (32 countries) for prostate cancer incidence and mortality, respectively. One other ecological study (47
), which assessed the correlation between prostate cancer mortality rates in Brazil and mean household energy intake from a national survey of a representative sample, did not observe a positive correlation. Overall, ecological studies indirectly suggest that energy intake related to prostate cancer incidence and mortality.
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The effects of energy restriction on prostate tumorigenesis were examined in only one study (40
). In that study, two transplantable prostate tumor models were used: the Dunning R3327-H rat adenocarcinoma, which was transplanted into rats, and the LNCaP human adenocarcinoma, which was transplanted into SCID mice. The former is an androgen-sensitive prostate cancer cell line that is moderately differentiated. The latter is also androgen sensitive but is poorly differentiated. The rodents were fed diets with energy restriction ranging from 20 to 40% (i.e., 80 and 60% of the usual energy intake). In general, the transplanted tumors were smaller, had increased stroma and smaller glands, had reduced expression of VEGF and had reduced microvessel density. The energy-restricted rodents also had lower circulating concentrations of IGF-1. These effects were observed irrespective of whether energy reduction came from fat, carbohydrate or total diet, suggesting that energy and not macronutrient contributors to energy was causative. Because these models consist of tumor-forming prostate cancer cell lines, these experiments exclusively address the effect of energy restriction on later phases in tumorigenesis.
Analytic epidemiologic studies.
Only one epidemiologic study (48
) examined the relation of energy restriction with prostate cancer. In that prospective study, men who were adolescents circa World War II and who lived in cities that experienced economic depression before World War II or experienced impaired nutrition and famine during World War II were considered to have been energy restricted. No association was observed. However, the authors point to several possible explanations: the duration of extreme restriction was relatively short (months), the contrast in energy restriction between cities may have been limited and the participants may already have been too old (
12 y) at the time of energy restriction for it to have affected prostate carcinogenesis. The authors did not raise the alternative explanation that perhaps the energy restriction was too early in the natural history of the prostate carcinogenesis to have an effect. Energy restriction during adolescence might have been ineffectual because too few of the boys may have had preneoplastic lesions present to enable the detection of the reduced promotion or progression effects of energy restriction.
Twenty-three distinct analytic epidemiologic studies—5 cohort (49
–53
) and 18 case-control (54
–71
)—have evaluated the association of energy intake with prostate cancer risk. Additional publications have included data on energy intake and prostate cancer (e.g., mean differences between cases and noncases), but these reported on the same study populations as earlier (50
and 72
; 56
and 73
; 62
and 74
). The authors reported a relative risk in 4 of the cohort studies (49
–52
) (Table 2
) and 14 of the case-control studies (54
–67
) (Table 3
). The authors reported means or gave a qualitative result in the remainder of the studies (53
,68
–71
) (Table 4
). Details of the study populations, methods used to assess energy intake, typical energy intake and other study features are given in Tables 2
–4
. Direct associations were reported in 8 (54
–56
,59
,61
,64
,66
,67
) of the 14 case-control studies and none of the 4 cohort studies (Fig. 1
). To summarize the findings of these studies, meta-analyses were performed separately for cohort and case-control studies. The exponential of the weighted average of the natural logarithm of the relative risks (lnRRs) was calculated, where the weights were the inverse of the standard error of the lnRR (75
). In the reviewed studies, the relative risks (RRs) across quantiles of energy intake were largely nonlinear on the natural logarithm scale. The RR for total prostate cancer that compared the highest with the lowest group of energy intakes was used rather than an estimate of the regression (logistic or Cox proportional hazards) coefficient from the presented RRs. The limitation of this approach is that the contrasts between high and low energy intake are more in extreme in the studies using a greater number of groups (quantiles or quartiles versus tertiles). The confidence interval for the Fincham et al. study (57
) was estimated from the presented data. In the West et al. study (67
), estimates were provided separately for younger and older men because the effect was strong in older men and not present in younger men.
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) in the effect estimates among the case-control studies [including older and younger men from West et al. (67
), P = 0.0006 and 0.0007, respectively] but not the cohort studies (P = 0.55).
On the basis of mouse and rat studies of energy restriction, excessive energy intake may act later in the natural history of prostate carcinogenesis. Thus studies that specifically evaluated the association of energy intake with advanced disease were considered separately to determine whether the association is stronger for this subset of cases. Three of the case-control studies reported ORs for advanced disease (54
,59
,67
). In addition, a case only study by Bairati et al. (76
) that compared advanced cases with local cases was included (Table 3)
. For the case-control studies there was evidence for a moderate positive association with advanced disease (Fig. 2
). A comparison of the highest with the lowest quantiles of energy intake gave an ORsummary of 1.6 (95% CI, 1.2–2.0) when including the older men and 1.5 (95% CI, 1.2–2.0) when including the younger men from the West et al. study (67
). Again there was statistically significant heterogeneity in the effect estimates in these studies (P = 0.004 and 0.005, respectively). The only cohort study that estimated the RR for advanced disease observed no association (RR = 0.9; 95% CI, 0.6–1.3) when extreme quintiles of energy intake were compared (51
).
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,78
). Neither study observed consistent evidence for a positive association (Table 5
). Although both of these studies were conducted prospectively, the number of men included in the studies (they were originally controls in prostate cancer case-control studies) and the number of prostate cancer deaths that occurred during the relatively short follow-up intervals led to great imprecision in the estimates.
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If the animal experiments clearly show that energy restriction reduces tumor burden overall and reduces indicators of prostate cancer cell growth in particular and if the descriptive epidemiologic studies (e.g., migrant and ecological studies) indirectly show that higher energy intake is associated with higher prostate cancer risk, then why are the findings for the analytic epidemiologic studies inconsistent, especially between the cohort and case-control studies? Four explanations may be considered. First, none of the epidemiologic studies have systematically considered the balance of energy input with energy demand. Second, few have examined the energy association separately by phases in the natural history of prostate cancer. Third, the extent of error in the measurement of energy intake may have differed among studies. Fourth, the timing of diet report relative to diagnosis has differed among studies.
Because the analytic epidemiologic studies were conducted in a wide array of settings, some populations may have had high energy intake but compensatory higher activity levels or were on average taller, whereas other populations may have had high energy intake but were sedentary or were shorter. Thus a higher energy intake may have been excessive in some studies but not in others. Studies of energy in relation to prostate cancer must therefore consider individual energy intake relative to body size and level of physical activity so that equivalent comparisons may be made within and between studies.
Because the extent of energy intake is likely a determinant of growth factor levels and excessive intake likely contributes to the promotion or progression of a tumor rather than its initiation, energy intake would be expected to have a greater effect on the transition to a clinically relevant stage, in particular, metastasis (Fig. 3
). Few studies have examined the association expressly for metastatic prostate cancer or death from prostate cancer, and typically the proportion of cases that are advanced is low. Thus the effect estimate for total prostate cancers that are due to the influence of energy on the subgroup of advanced cases is unlikely to be statistically detectable. Furthermore, studies conducted solely during the era when prostate-specific antigen has been available for widespread screening are very unlikely to find associations for energy because most detected lesions are small and of low-to-moderate histologic grade.
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). However, FFQs tend to underestimate energy intake by 10–30% (6
). The extent of the underestimation depends in part on the number of foods listed on the FFQ. Some studies on energy intake and prostate cancer used an FFQ with >120 foods, whereas others used FFQs with half as many foods (Tables 2
and 3)
. In populations that eat a wide array of foods, FFQs might not fully capture total energy intake but would be expected to rank individuals of similar body size and activity level correctly for energy intake. That is, those who tend to eat more would be ranked higher than those who eat less even though reported intake is underestimated for everyone. However, obese individuals tend to underreport energy intake more than normal-weight individuals (80
). This means that in analyses of the relation of energy and prostate cancer, body size should be considered to reduce error in the measurement of energy intake. Diet was retrospectively assessed in the case-control control studies, whereas in the cohort studies diet was reported months to years before prostate cancer diagnosis. If the men with prostate cancer overreported their past dietary intake but control subjects accurately reported their past intake, then in the case-control studies energy would be falsely associated with a higher risk of prostate cancer. Also, if case subjects with metastatic disease were experiencing wasting and began to eat more and if these men incorrectly reported on their current rather than prediagnosis diet and the control subjects reported accurately on their diet, then higher energy intake would appear to be a risk factor for prostate cancer. However, as described earlier, the proportion of men with metastatic prostate cancer in these studies was typically small. Thus it is very unlikely that misreporting by a small percentage of the most severe cases would distort the overall association. Another possible explanation for the differences in findings between the case-control and cohort studies is derived from differences in the timing of diet relative to the etiologically relevant moment. In the case-control studies diet was assessed proximal to prostate cancer diagnosis whereas in the cohort studies, the diet was assessed up to 6–23 y before diagnosis. If energy acts late in prostate carcinogenesis, then it is possible that the cohort studies, although the preferred approach to avoiding bias in the measurement of exposure that is differential by outcome, the assessment of exposure was too far before the most etiologically relevant moment.
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Future directions |
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TOPABSTRACTINTRODUCTIONOverview of energy restriction...Evidence that energy imbalance...Future directionsLITERATURE CITED |
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Research needs.
First, are appropriate animal models of prostate carcinogenesis available in which to explore the effect of energy? Implantable tumor models were used in the only experimental study of energy restriction and prostate cancer published to date. This study is very informative about the role of energy restriction on further tumor growth and neovascularization, that is, on the later events in prostate carcinogenesis. Additional models of early stages of prostate carcinogenesis are needed so that the full range of the effects of energy may be assessed. In addition, models are needed to provide data on the effect of energy restriction on the intact prostate. Stromal–epithelial interactions in the prostate and feedback mechanisms between the prostate and other organs that modulate the effects of energy restriction, which are not present in the transplantable models, are likely important players in prostate carcinogenesis. Rat and mouse models of prostate cancer development in the intact organ include testosterone- and estrogen-promoted prostatic intraepithelial neoplasia in rats, which is a model for very early steps in carcinogenesis; mutagen-initiated prostate tumors, which are models for early stage carcinogenesis; and the transgenic TRAMP mouse (expresses SV40 large T antigen in the prostate), a model for the entire spectrum of prostate carcinogenesis, including metastasis (81
). Even these models may be inadequate for assessing the effects of energy imbalance on prostate cancer because of the differences in structure of the prostate in mouse and rat compared with humans. Mouse and rat models that spontaneously develop prostate cancer with frequencies equivalent to that in humans do not exist (81
).
Second, additional analytic epidemiologic studies of energy imbalance and prostate cancer risk in large cohorts with long-term follow-up are needed. Prostate cancer cases must be well characterized and include a substantial number of advanced cases, in particular cases with distant metastases and fatal cases, so that comparisons of the effect of energy can be determined across the spectrum of disease. Energy intake should be prospectively assessed and adequately measured at baseline and over the course of follow-up so that both past and recent energy intake may be evaluated. These studies should also evaluate the association between energy intake and prostate cancer after taking into account differences in body size and activity levels, both occupational and leisure time.
Research questions.
Which biological pathways are adversely affected by energy imbalance? Defining which pathways are affected will allow for the development of specific interventions. In addition to examining the endocrine effects of energy restriction (e.g., effects on circulating concentrations of growth factors such as IGF-I), how energy imbalance interferes with the paracrine regulation of normal prostate growth should be explored. In the prostate, endothelial cells (vessel) produce growth factors, including IGF-I, which together with androgenic stimulation cause the prostate epithelium to produce angiogenic factors, such as VEGF (22
). Expression profiling may provide clues for the link between energy imbalance and risk of prostate cancer. Cao et al. (82
) demonstrated differential up- and down-regulation of genes with energy restriction compared with control in the mouse liver, including those involved in energy metabolism and biosynthesis, apoptosis and cell growth and survival and intracellular signaling (82
). They also compared the expression patterns with those previously published for other energy-restricted tissues and noted tissue specificity. The specificity of gene expression among tissues indicates that differential expression studies are needed for the prostate. Separate profiling for epithelial and stromal components of normal and malignant prostate tissue, which is best accomplished by laser capture microdissection, is essential to learn more about autocrine and paracrine activities of energy imbalance.
Precisely when in the prostate carcinogenesis pathway does energy imbalance act?
Although emerging evidence points to energy acting late in carcinogenesis, experimental studies should address whether in the prostate energy imbalance influences only progression or also promotion and initiation. In a model of hepatocellular carcinoma in the rat, energy restriction during the progression phase of carcinogenesis after mutagen initiation and promotion by partial hepatectomy was effective in reducing liver carcinogenesis (17
). Earlier studies of liver tumors and energy restriction of 40–60% encompassing both promotion and progression also resulted in tumor inhibition (17
). High energy intake may contribute to excessive inflammatory response in tissues such as the lung. With energy restriction, inflammation is reduced but appropriate immune response to a challenge is not impaired (83
). The production of reactive oxygen species generated during the inflammatory response likely would contribute to the initiation phase of carcinogenesis. Whether energy imbalance contributes to proliferative inflammatory atrophy, a possible very early precursor lesion for prostate cancer (84
), should be examined.
What times in life are critical for the adverse effect of energy imbalance: early life, adolescence and puberty, midlife or older years?
Related to the question of when energy imbalance acts in prostate carcinogenesis is this practical question for designing interventions. Experimental studies for tumors other than prostate have observed benefits of energy restriction started in both early life [just after weaning (85
)] and midlife (27
,86
). Other studies suggest that energy restriction late in life is ineffective (87
).
What is the optimal energy balance for minimizing risk of clinically important prostate cancer?
Animal studies with other tumor end points typically have used energy restriction to 20–40% of usual consumption of free-access diet. One study systematically examined energy restriction throughout the range of 10–40% in carcinogen-initiated mammary tumors in female rats (42
). The incidence of mammary tumors declined starting at 20% restriction, but tumor multiplicity and tumor weight declined starting at 10% restriction. The translation of findings from animal models of energy restriction and prostate carcinogenesis will be complex but essential for affecting the high rates of prostate cancer in Western countries and the rising rates of prostate cancer in formerly low-risk countries.
Which patterns of energy imbalance reduce and which enhance prostate carcinogenesis?
Thompson et al. (41
) described three experimental patterns of energy restriction that mimic human dieting patterns: sustained energy restriction to avoid weight gain, energy restriction to lose weight after maintenance of new a lower weight and cyclical energy restriction and refeeding corresponding to weight loss and regain. The classic mouse and rat models of energy restriction fall into the first two patterns. In some models the benefit of energy restriction on enhancing apoptosis is lost or attenuated after free-access refeeding. In a model of liver carcinogenesis, refeeding after energy restriction resulted in less apoptosis and more preneoplastic lesions, both equivalent to control levels (88
). In a mutagen-initiated mammary tumor model in the rat, 3 cycles of fasting followed by refeeding enhanced tumorigenesis (89
). In p53 (+/-) mice, a model of delay in the onset of carcinogenesis, fasting followed by controlled intake on the nonfasting days to avoid overeating caused a delay in onset of tumors that was intermediate between free-access feeding and energy restriction of 60% of free-access consumption (27
). Fasting followed by free-access refeeding may not be as effective in impeding tumorigenesis because of compensatory cell proliferation to counter prior higher levels of apoptosis during the energy restriction phase (17
). A wide array of patterns of fasting followed by refeeding, including the length of each interval and the number of cycles, has been used in experimental studies. To understand the effect of fasting and refeeding on prostate carcinogenesis, standard patterns must be evaluated. In addition, the timing of the cycles of fasting and refeeding relative to the experimental phases of prostate carcinogenesis must be considered. For example, in a study of mutagen-initiated mammary carcinogenesis in the rat, fasting and refeeding during the promotional phase (after administration of the mutagen) but not the initiation phase (before administration of the mutagen) resulted in a greater number of mammary tumors (90
).
What are the effects of energy imbalance on survival with prostate cancer? If energy imbalance acts later in the natural history of prostate cancer, then it might be hypothesized that survival with prostate cancer would be worse in men who were in energy imbalance because they would be more likely to experience greater tumor growth and metastasis. The two published epidemiologic studies addressing this question used optimal designs (prospective studies), but because of small sample size and short follow-up time they yielded very imprecise estimates of effect. Additional follow-up of these men may prove informative. Because death from prostate cancer is now substantially less common, large cohorts of men with prostate cancer for whom prediagnosis diet as well as postdiagnosis diet data have been collected are needed to address whether energy intake influences the progression of prostate cancer to distant metastases and death.
Laboratory and epidemiologic evidence is beginning to support the hypothesis that higher energy intake relative to energy demand influences the growth of prostate tumors and enhances dissemination of prostate tumor metastases. However, much work in experimental and observational studies remain to be done to elucidate fully its etiologic role. Defining the effect of energy imbalance on prostate cancer and other conditions is of particular importance now because the United States is experiencing an epidemic of obesity in children as well as in adults; about 60% of adults are overweight or obese (91
,92
). The marked increase in the prevalence of obesity may be in part due to the rapid increase in total energy intake by Americans of all ages over the past 20 y (93
). The prevalence of obesity is also rising globally (94
), including in children and adolescents (95
). If energy imbalance does influence prostate carcinogenesis, without intervention prostate cancer rates may substantially rise internationally.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Dr. Platz is partially supported by the Bernstein Young Investigator’s Award.
4 Abbreviations used: FFQ, food frequency questionnaire; IGF, insulin-like growth factor; lnRRs, natural logarithm of the relative risks; VEGF, vascular endothelial growth factor.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONOverview of energy restriction...Evidence that energy imbalance...Future directionsLITERATURE CITED |
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1. Jemal, A., Thomas, A., Murray, T. & Thun, M. (2002) Cancer statistics. CA Cancer J. Clin. 52:23-47.
2. Platz, E. A., Kantoff, P. W. & Giovannucci, E. () Epidemiology of and risk factors for prostate cancer: diet, genetics, and racial variation. Klein, E. eds. Current Clinical Urology: Management of Prostate Cancer :19-45 Humana Press Totowa, NJ .
3. Platz, E. A. & Helzlsouer, K. J. (2001) Selenium, zinc, and prostate cancer. Epidemiol. Rev. 23:93-101.
4. Giovannucci, E., Rimm, E. B., Liu, Y., Stampfer, M. J. & Willett, W. C. (2002) A prospective study of tomato products, lycopene, and prostate cancer risk. J. Natl. Cancer Inst. 94:391-398.
5. Hsing, A. W., Deng, J., Sesterhenn, I. A., Mostofi, F. K., Stanczyk, F. Z., Benichou, J., Xie, T. & Gao, Y. T. (2000) Body size and prostate cancer: a population-based case-control study in China. Cancer Epidemiol. Biomarkers Prev. 9:1335-1341.
6. Willett, W. C. (1998) Nutritional Epidemiology 1998 Oxford University Press New York .
7. Ravussin, E., Lillioja, S., Anderson, T. E., Christin, L. & Bogardus, C. (1986) Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J. Clin. Invest. 78:1568-1578.
8. Willett, W. C., Manson, J. E., Stampfer, M. J., Colditz, G. A., Rosner, B., Speizer, F. E. & Hennekens, C. H. (1995) Weight, weight change, and coronary heart disease in women. Risk within the ’normal’ weight range. J. Am. Med. Assoc. 273:461-465.
9. Rimm, E. B., Stampfer, M. J., Giovannucci, E., Ascherio, A., Spiegelman, D., Colditz, G. A. & Willett, W. C. (1995) Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am. J. Epidemiol. 141:1117-1127.
10. Bergstrom, A., Pisani, P., Tenet, V., Wolk, A. & Adami, H. O. (2001) Overweight as an avoidable cause of cancer in Europe. Int. J. Cancer 91:421-430.[Medline]
11. Manson, J. E., Willett, W. C., Stampfer, M. J., Colditz, G. A., Hunter, D. J., Hankinson, S.E., Hennekens, C. H. & Speizer, F. E. (1995) Body weight and mortality among women. N. Engl. J. Med. 333:677-685.
12. Baik, I., Ascherio, A., Rimm, E. B., Giovannucci, E., Spiegelman, D., Stampfer, M. J. & Willett, W. C. (2000) Adiposity and mortality in men. Am. J. Epidemiol. 152:264-271.
13. Kritchevsky, D. (1999) Caloric restriction and experimental carcinogenesis. Toxicol. Sci. 52(suppl.):13-16.
14. Thompson, H. J., Jiang, W. & Zhu, Z. (1999) Mechanisms by which energy restriction inhibits carcinogenesis. Adv. Exp. Med. Biol. 470:77-84.[Medline]
15. Zhu, Z., Haegele, A. D. & Thompson, J. H. (1997) Effect of caloric restriction on pre-malignant and malignant stages of mammary carcinogenesis. Carcinogenesis 18:1007-1012.
16. Hanahan, D. & Weinberg, R. A. (2000) The hallmarks of cancer. Cell 100:57-70.[Medline]
17. Wang, G. S., Olsson, J. M., Eriksson, L. C. & Stal, P. (2000) Diet restriction increases ubiquinone contents and inhibits progression of hepatocellular carcinoma in the rat. Scand. J. Gastroenterol. 35:83-89.[Medline]
18. Gallaher, B. W., Hille, R., Raile, K. & Kiess, W. Apoptosis. (2001) Live or die: hard work either way!. Horm. Metab. Res. 33:511-519.[Medline]
19. Igney, F. H. & Krammer, P. H. (2002) Death and anti-death: tumour resistance to apoptosis. Nat. Rev. 2:277-288.
20. Zhu, Z., Jiang, W. & Thompson, H. J. (1999) Effect of energy restriction on tissue size regulation during chemically induced mammary carcinogenesis. Carcinogenesis 20:1721-1726.
21. Hursting, S. D., Perkins, S. N., Phang, J. M. & Barrett, J. C. (2001) Diet and cancer prevention studies in p53-deficient mice. J. Nutr. 131:3092S-3094S.
22. Folkman, J. (1998) Is tissue mass regulated by vascular endothelial cells? Prostate as the first evidence (editorial). Endocrinology 139:441-442.
23. Carmeliet, P. & Jain, R. K. (2000) Angiogenesis in cancer and other diseases. Nature 407:249-257.[Medline]
24. Semenza, G. L. (2002) HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med. 8(suppl.):S62-S67.[Medline]
25. Adams, T. E., Epa, V. C., Garrett, T. P. J. & Ward, C. W. (2000) Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol. Life Sci. 57:1050-1093.[Medline]
26. Grimberg, A. & Cohen, P. (2000) Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J. Cell. Physiol. 183:1-9.[Medline]
27. Berrigan, D., Perkins, S. N., Haines, D. C. & Hursting, S. D. (2002) Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis 23:817-822.
28. Dunn, S. E., Kari, F. W., French, J., Leininger, J. R., Travlos, G., Wilson, R. & Barrett, J. C. (1997) Dietary restriction reduces insulin-like growth factor-1 levels which modulates apoptosis, cell proliferation, and tumor progression in p53 deficient mice. Cancer Res 57:4667-4672.
29. Kari, F. W., Dunn, S. E., French, J. E. & Barrett, J. C. (1999) Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. J. Nutr. Health Aging 3:92-100.[Medline]
30. Cohen, P., Peehl, D. M., Lamson, G. & Rosenfeld, R. G. (1991) Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J. Clin. Endocrinol. Metab. 73:401-407.[Abstract]
31. Wang, Y. Z. & Wong, Y. C. (1998) Sex hormone-induced prostatic carcinogenesis in the Noble rat: the role of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate 35:165-177.[Medline]
32. Cohen, P., Clemmons, D. R. & Rosenfeld, R. G. (2000) Does the GH-IGF axis play a role in cancer pathogenesis?. Growth Horm. IGF Res. 10:297-305.[Medline]
33. Shi, R., Berkel, H. J. & Yu, H. (2001) Insulin-like growth factor-I and prostate cancer: a meta-analysis. Br. J. Cancer 85:991-996.[Medline]
34. Kaaks, R. & Lukanova, A. (2001) Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc. Nutr. Soc. 60:91-106.[Medline]
35. Clemmons, D. R., Klibanski, A., Underwood, L. E., McArthur, J. W., Ridgway, E. C., Beitins, I. Z. & Van Wyk, J. J. (1981) Reduction of plasma immunoreactive somatomedin C during fasting in humans. J. Clin. Endocrinol. Metab. 53:1247-1250.[Abstract]
36. Isley, W. L., Underwood, L. E. & Clemmons, D. R. (1983) Dietary components that regulate serum somatomedin-C concentrations in humans. J. Clin. Invest. 71:175-182.
37. Youngman, L. D., Park, J. Y. K. & Ames, B. N. (1992) Protein oxidation associated with aging is reduced by dietary restriction of protein or calories. Proc. Natl. Acad. Sci. U.S.A. 89:9112-9116.
38. Yu, B. P. & Chung, H. Y. (2001) Stress resistance by caloric restriction for longevity. Ann. N.Y. Acad. Sci. 928:39-47.
39. Koohestani, N., Chia, M. C., Pham, N. A., Tran, T. T., Minkin, S., Wolever, T. M. S. & Bruce, W. R. (1998) Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids, and energy. Carcinogenesis 19:1679-1684.
40. Mukherjee, P., Sotnikov, A. V., Mangian, H. J., Zhou, J. R., Visek, W. J. & Clinton, S. K. (1999) Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J. Natl. Cancer Inst. 91:512-523.
41. Thompson, H. J., Zhu, Z. & Jiang, W. (2002) Protection against cancer by energy restriction: all experimental approaches are not equal. J. Nutr. 132:1047-1049.
42. Klurfeld, D. M., Welch, C. B., Davis, M. J. & Kritchevsky, D. (1989) Determination of energy restriction necessary to reduce DMBA-induced mammary tumorigenesis in rats during the promotion phase. J. Nutr. 119:286-291.
43. Haenszel, W. & Kurihara, M. (1968) Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J. Natl. Cancer Inst. 40:43-68.
44. Armstrong, B. & Doll, R. (1975) Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int. J. Cancer 15:617-631.[Medline]
45. Hebert, J. R., Hurley, T. G., Olendzki, B. C., Teas, J., Ma, Y. & Hampl, J. S. (1998) Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J. Natl. Cancer Inst.. 90:1637-1647.
46. Rose, D. P., Boyar, A. P. & Wynder, E. L. (1986) International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 58:2363-2371.[Medline]
47. Sichieri, R., Everhart, J. & Mendonca, G. (1996) Diet and mortality from common cancers in Brazil: an ecological study. Cad. Saude Publica 12:53-59.[Medline]
48. Dirx, M. J. M., van den Brandt, P. A., Goldbohm, R. A. & Lumey, L. H. (2001) Energy restriction in childhood and adolescence and risk of prostate cancer: results from the Netherlands Cohort Study. Am. J. Epidemiol. 154:530-537.
49. Severson, R. K., Nomura, A. M. Y., Grove, J. S. & Stemmermann, G. N. (1989) A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res 49:1857-1860.
50. Veierod, M. B., Laake, P. & Thelle, D. S. (1997) Dietary fat intake and risk of prostate cancer: a prospective study of 25,708 Norwegian men. Int. J. Cancer 73:634-638.[Medline]
51. Schuurman, A. G., van den Brandt, P. A., Dorant, E., Brants, H. A. & Goldbohm, R. A. (1999) Association of energy and fat intake with prostate carcinoma risk: results from the Netherlands Cohort Study. Cancer 86:1019-1027.[Medline]
52. Chan, J. M., Pietinen, P., Virtanen, M., Malila, N. & Tangrea, J. (2000) Diet and prostate cancer risk in a cohort of smokers, with a specific focus on calcium and phosphorus (Finland). Cancer Causes Control 11:859-867.[Medline]
53. Frankel, S., Gunnell, D. J., Peters, T. J., Maynard, M. & Smith, G. D. (1998) Childhood energy intake and adult mortality from cancer: the Boyd Orr cohort study. Br. Med. J. 316:499-504.
54. Andersson, S. O., Wolk, A., Bergstrom, R., Giovannucci, E., Lindgren, C., Baron, J. & Adami, H. O. (1996) Energy, nutrient intake and prostate cancer risk: a population-based case-control study in Sweden. Int. J. Cancer 68:716-722.[Medline]
55. Bairati, I., Larouche, R., Meyer, F., Moore, L. & Fradet, Y. (2000) Lifetime occupational physical activity and incidental prostate cancer. Cancer Causes Control 11:759-764.[Medline]
56. Deneo-Pellegrini, H., De Stefani, E., Ronco, A. & Mendilaharsu, M. (1999) Foods, nutrients and prostate cancer: a case-control study in Uruguay. Br. J. Cancer 80:591-597.[Medline]
57. Fincham, S. M., Hill, G. B., Hanson, J. & Wijayasinghe, C. (1990) Epidemiology of prostatic cancer: a case-control study. Prostate 17:189-206.[Medline]
58. Ghadirian, P., Lacroix, A., Maisonneuve, P., Perret, C., Drouin, G., Perrault, J. P., Beland, G., Rohan, T. E. & Howe, G. R. (1996) Nutritional factors and prostate cancer: a case-control study of French Canadians in Montreal, Canada. Cancer Causes Control 7:428-436.[Medline]
59. Hayes, R. B., Ziegler, R. G., Gridley, G., Swanson, C., Greenberg, R. S., Swanson, G. M., Schoenberg, J. B., Silverman, D. T., Brown, L. M., Pottern, L. M., Liff, J., Schwartz, A. G., Fraumeni, J. F., Jr & Hoover, R. N. (1999) Dietary factors and risks for prostate cancer among blacks and whites in the United States. Cancer Epidemiol. Biomarkers Prev. 8:25-34.
60. Key, T. J. A., Silcocks, P. B., Davey, G. K., Appleby, P. N. & Bishop, D. T. (1997) A case-control study of diet and prostate cancer. Br. J. Cancer 76:678-687.[Medline]
61. Meyer, F., Bairati, I., Fradet, Y. & Moore, L. (1997) Dietary energy and nutrients in relation to preclinical prostate cancer. Nutr. Cancer 29:120-126.[Medline]
62. Oishi, K., Okada, K., Yoshida, O., Yamabe, H., Ohno, Y., Hayes, R. & Schroeder, F. H. (1988) A case-control study of prostatic cancer with reference to dietary habits. Prostate 12:179-190.[Medline]
63. Ramon, J. M., Bou, R., Romea, S., Alkiza, M. E., Jacas, M., Ribes, J. & Oromi, J. (2000) Dietary fat intake and prostate cancer risk: a case-control study in Spain. Cancer Causes Control 11:679-685.[Medline]
64. Rohan, T. E., Howe, G. R., Burch, J. D. & Jain, M. (1995) Dietary factors and risk of prostate cancer: a case-control study in Ontario, Canada. Cancer Causes Control 6:145-154.[Medline]
65. Villeneuve, P. J., Johnson, K. C., Kreiger, N. & Mao, Y., The Canadian Cancer Registries Epidemiology Research Group (1999) Risk factors for prostate cancer: results from the Canadian National Enhanced Cancer Surveillance System. Cancer Causes Control 10:355-367.[Medline]
66. Vlajinac, H. D., Marinkovic, J. M., Ilic, M. D. & Kocev, N. I. (1997) Diet and prostate cancer: a case-control study. Eur. J. Cancer 33:101-107.
67. West, D. W., Slattery, M. L., Robison, L. M., French, T. K. & Mahoney, A. W. (1991) Adult dietary intake and prostate cancer risk in Utah: a case-control study with special emphasis on aggressive tumors. Cancer Causes Control 2:85-94.[Medline]
68. Kaul, L., Heshmat, M. Y., Kovi, J., Jackson, M. A., Jackson, A. G., Jones, G. W., Edson, M., Enterline, J. P., Worrell, R. G. & Perry, S. L. (1987) The role of diet in prostate cancer. Nutr. Cancer 9:123-128.
