ABSTRACT
Human epidemiology suggests a protective effect of tomatoes or tomato phytochemicals, such as lycopene, on prostate cancer risk. However, human epidemiology alone cannot reveal causal relations. Laboratory animal models of prostate cancer provide opportunities to investigate hypotheses regarding dietary components in precisely controlled, experimental systems, contributing to our understanding of diet and cancer risk relations. We review the published studies evaluating the impact of tomatoes and/or lycopene in preclinical models of prostate carcinogenesis and tumorigenesis. The feeding of tomatoes or tomato components demonstrates anti–prostate cancer activity in both transplantable xenograft models of tumorigenesis and models of chemically- and genetically-driven carcinogenesis. Feeding pure lycopene shows anticancer activity in most studies, although outcomes vary by model system, suggesting that the impact of pure lycopene can depend on dose, duration, and specific carcinogenic processes represented in different models. Nonetheless, studies with the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of carcinogenesis typically demonstrate similar bioactivity to that of tomato feeding. In general, interventions that commence earlier in carcinogenesis and are sustained tend to be more efficacious. Accumulated data suggest that lycopene is one, but perhaps not the only, anticancer bioactive compound in tomatoes. Although it is clear that tomatoes and lycopene have anti–prostate cancer activity in rodent models, major knowledge gaps remain in understanding dose–response relations and molecular mechanisms of action. Published and future findings from rodent studies can provide guidance for translational scientists to design and execute informative human clinical trials of prostate cancer prevention or in support of therapy.
Keywords: preclinical models, nutrition, prostate carcinogenesis, tomato, prostate metastasis
Introduction
The hypothesis that consuming tomatoes and the tomato carotenoid lycopene can be protective against prostate cancer was established following landmark observations from the Health Professionals Follow-up Study (HPFS) published in 1995 (1). Subsequent updates from this prospective cohort of 50,000 men continue to support a relation (2, 3) but with some added clarity. Prostate cancer is a heterogeneous family of diseases, and the protective benefit of tomato products is stronger for the more aggressive and lethal subtypes (2, 3). Yet, the hypothesis that long-term intake of tomatoes and tomato phytochemicals can reduce prostate cancer risk remains a topic of debate (4–7), with shifting interpretations arising from the literature as more epidemiological studies are considered and as prostate cancer screening and detection strategies change over time (6–11). Thus, future epidemiological studies integrating the molecular and biological subtypes of prostate cancer into the analysis could provide greater precision regarding a preventive potential of tomato products (2, 3, 12). In addition, the difficulty of estimating human exposure to tomato bioactive compounds over the years necessary to understand the impact on human prostate carcinogenesis is appreciated. The combination of diversity in tomato varieties and food products consumed, coupled with the host variation in absorption and metabolism provides a challenge for epidemiological efforts (1–3, 13, 14). Thus, establishing a causal relation with cancer risk for such a widely consumed food with population studies alone might not be possible.
Ultimately, human intervention studies are desired to assess the potential of tomato products, lycopene, or other pure bioactive components to impact prostate carcinogenesis. To date, published human intervention studies are of short duration, conducted mostly in men with established cancers, and have focused upon studying lycopene absorption and tissue distribution, as well as cancer-related biomarkers such as rates of prostate specific antigen (PSA) changes (15–25). To invest in future informative studies of human prostate cancer prevention, it is necessary to justify such expensive efforts through a far greater understanding of the mechanisms of action and conditions impacting lycopene or tomato bioactivity. Such factors to consider for future human studies in a high-risk cohort could include age, genetic predisposition, presence of high-grade prostatic intraepithelial neoplasia (PIN) or low-grade cancers, or elevated PSA with a negative biopsy. The optimal delivery method such as food compared with pure lycopene, the appropriate dose level, and duration and timing of treatment are also key issues to consider for human translation.
Preclinical rodent studies can provide insight into subpopulations worthy of study and inform study designs for intervention. Rodent models of prostate cancer serve as a valuable resource for testing foods and derived fractions, as well as pure bioactive compounds, providing an opportunity to assess toxicology and safety, biodistribution, anticancer activity, and mechanisms of action. Here we review the evidence from 21 published rodent model studies that examined the impact of different doses of tomatoes, tomato components, or lycopene on histopathological and/or tumor burden outcomes of prostate cancer, which are outcomes that can be related to similar outcomes in humans. No single rodent model of prostate cancer completely mimics the characteristics of human prostate cancer (26–28), which exhibits diverse molecular genetic defects (29, 30) associated with different rates of progression and sensitivities to therapeutic interventions. However, specific rodent models of prostate cancer demonstrate predictable pathology and rates of progression, providing insight into the effects of preventive or therapeutic interventions on specific pathophysiological mechanisms of prostate carcinogenesis or tumor growth. It is anticipated that preclinical studies can guide the development of human intervention trials by assessing biological plausibility, identifying biomarkers related to mechanisms of action, and providing insight regarding the dose-dependent relations between whole foods or pure phytochemicals and anticancer efficacy.
Lycopene: A Key Tomato Bioactive Compound
Blood lycopene concentrations are indicative of tomato product intake but can also serve as a marker of a particular overall dietary pattern that is rich in plant foods. Whereas the HPFS study initially revealed an inverse relation between dietary tomato consumption and prostate cancer risk, subsequent epidemiological studies have employed blood lycopene concentrations as a biomarker of dietary tomato carotenoid exposure. Blood and skin carotenoid concentrations are broadly used as a biomarker of fruit and vegetable intake in human research (31, 32). To determine if lycopene itself is a key bioactive compound, several preclinical studies have directly compared the effects of lycopene with whole tomato feeding (33–36). Indeed, tomatoes and tomato-based products contain an array of phytochemicals including carotenoids, polyphenols, and nutrients, such as vitamins C and E and potassium. Among the tomato carotenoids, lycopene, a 40-carbon carotenoid with 11 conjugated double bonds, has drawn the most attention because of its relative abundance in tomatoes, its well-known antioxidant properties (8, 37, 38), and other bioactive functions detailed below. Although it is unlikely that the entire biological impact of tomato product intake is due to 1 component, rodent studies comparing lycopene with tomato powder feeding suggest that lycopene is active in modulating early prostate carcinogenesis (36, 39). Studies suggest similar effects of tomato and lycopene on gene expression patterns and tumor incidence in the transgenic adenoma of the mouse prostate (TRAMP) model (36, 39). Alternatively, whole tomato powder was more effective than lycopene alone in the Dunning rat model of implanted tumor growth and in a large study of the N-methyl-N-nitrosourea (NMU)- and testosterone-driven model of rat carcinogenesis (33, 34). Given so few models have been examined, it is difficult to define which molecular features of cancer confer sensitivity to lycopene or tomato products. Although there are numerous phytochemicals found in tomatoes, to date, other than lycopene, only the ketosamine, fructose-histidine (FruHis), found in some processed tomato products (40), has been carefully compared with the effect of whole tomato; the relative effects of other tomato components in prostate carcinogenesis are unknown.
Animal Models Used to Study Prostate Cancer
A number of reviews of animal models of prostate cancer are available (27, 28, 41–46), including a comprehensive review of the pathological features of available genetically engineered mouse (GEM) models by the National Cancer Institute's Mouse Models of Human Cancers Consortium Prostate Cancer Steering Committee (26). For the reference of the reader, the different animal models discussed in the current review are summarized in Table 1. Briefly, rodent models can be broadly categorized as spontaneous carcinogenesis, chemical- and androgen-induced carcinogenesis, genetically engineered carcinogenesis, syngeneic transplantable tumorigenesis, and xenograft transplantable tumorigenesis models. The carcinogenesis models, including spontaneous, inducible, and genetically engineered systems, can demonstrate the entire initiation, promotion, progression, and metastatic spectrum of carcinogenesis, allowing investigators to probe the impacts of interventions on specific phases of cancer. Interventions in these systems are useful in assessing the delay or prevention of cancer in the context of the molecular drivers of those models. Tumorigenesis models involve the transplantation of either pieces of established tumors or inoculation with tumor-forming in vitro cancer lines. Syngeneic systems are cancers derived from and transplanted within the same genetic strain of mice or rats. Xenografts employ immune-compromised mice that will accept tumors or cells with entirely different genetic backgrounds and frequently will involve the use of human cancer cell lines. These models allow investigation of the impact of an intervention on tumor growth rates. As our understanding of the different molecular and histopathological features of prostate cancer has evolved, the different underlying mechanisms of prostate carcinogenesis, relapse, and metastasis modeled by each of the animal models and their potential limitations, are better appreciated. As new models are made available, their utility in testing specific mechanistic hypotheses related to tomato, lycopene, and prostate cancer prevention should be investigated.
TABLE 1.
Representative rodent models of prostate cancer utilized to study the effects of tomato and lycopene feeding1
| Model type | Model name | System |
|---|---|---|
| Inducible | Wistar rat | NMU ± testosterone ± cyproterone acetate; DMAB |
| F344 rat | DMAB | |
| DMAB ± testosterone | ||
| PhIP | ||
| Transgenic | TRAMP mouse | Probasin promoter drives expression of SV40 large and small T antigen; castration after tumor formation can be added to model castrate-resistant prostate cancer |
| Lady mouse | Probasin promoter drives expression of SV40 large T antigen | |
| Transplantable | Copenhagen rat | Dunning, R3327-H line |
| Copenhagen rat | Dunning, Mat-LyLu line | |
| Xenograft | Nude, SCID, NOD-SCID mice | Multiple human cell lines: PC-3, DU145, PC-346C |
Studies of tomato components or lycopene on prostate cancer in rodent models
Experimental models have been used to assess the ability of dietary tomato or lycopene to impact prostate carcinogenesis (12 studies) or tumorigenesis (9 studies), as detailed below. Although the quality of study design details reported varies substantially between publications (Tables 2 and 3), the following sections seek to contextualize the outcomes of each study. Indeed, to make the comparison of study findings more efficient, future publications should strive to comply with current guidelines for animal research reporting (47), with a particular focus on clearly and comprehensively reporting the dietary composition, defining the bioactive composition of the test agents, and reporting biomarkers of dietary exposure in the animal model, such as serum or tissue lycopene concentrations.
TABLE 2.
Effects of tomato or lycopene feeding, with or without other dietary components, compared with control diet on cancer outcomes in rat models of carcinogenesis, listed in chronological order1
| Study | Model | Dietary intervention | Tomato or lycopene source, mg lycopene/kg diet | Intervention timing | Group size, n | Plasma lycopene, μmol/L | Tissue lycopene, nmol/g | Cancer outcome measured | Cancer outcome results |
|---|---|---|---|---|---|---|---|---|---|
| Imaida (2001) (48) | Rat, F344 DMAB2 | Tomato extract–supplemented diet vs. control | LycoRed,2 15 mg lycopene/kg diet | During DMAB exposure (20 wk) | 19 | Not reported | Not reported | Ventral prostate and seminal vesicles. Atypical hyperplasia and carcinoma | NS2 |
| Tomato extract–supplemented diet vs. control | LycoRed, 15 mg lycopene/kg diet | After DMAB exposure (40 wk) | 18 | Not reported | Not reported | Ventral prostate and seminal vesicles. Atypical hyperplasia and carcinoma | Decreased PIN incidence (P < 0.05) | ||
| Imaida (2001) (48) | Rat, F344 DMAB | Tomato extract–supplemented diet vs. control | LycoRed, 5 mg lycopene/kg diet | After DMAB exposure (40 wk) | 17 | <0.019 | Liver: 4.90 ± 2.96 | Ventral prostate and seminal vesicles. PIN and carcinoma | NS |
| Tomato extract–supplemented diet vs. control | LycoRed, 15 mg lycopene/kg diet | After DMAB exposure (40 wk) | 17 | 0.019 | Liver: 14.62 ± 3.52 | Ventral prostate and seminal vesicles. PIN and carcinoma | NS | ||
| Tomato extract–supplemented diet vs. control | LycoRed, 45 mg lycopene/kg diet | After DMAB exposure (40 wk) | 16 | 0.037 ± 0.019 | Liver: 26.02 ± 4.11 | Ventral prostate and seminal vesicles. PIN and carcinoma | NS | ||
| Imaida (2001) (48) | Rat, F344 PhIP | Tomato extract–supplemented diet vs. control | LycoRed, 45 mg lycopene/kg diet | After PhIP exposure (50 wk) | 19 | Not reported | Not reported | Anterior and ventral prostate and seminal vesicle. PIN and carcinoma | NS |
| Boileau (2003) (33)3 | Rat, Wistar-Unilever NMU, testosterone | Lycopene vs. control | Lycopene beadlets,4 161 mg lycopene/kg diet | 67 wk, during and after carcinogen exposure | 11–19 | 0.118 | Not reported | Prostate cancer–specific survival | NS |
| 10% tomato powder supplemented diet vs. control | Spray-dried tomato paste,5 13 mg lycopene/kg diet | 67 wk ad lib, during and after carcinogen exposure | 11–19 | 0.085 | Not reported | Increased survival with tomato powder feeding (main effect; HR = 0.74; 95% CI: 0.59, 0.93; P = 0.009) | |||
| Mossine (2008) (40) | Rat, Wistar-Unilever NMU, testosterone | 10% tomato paste–supplemented diet vs. control | Tomato paste solids,6 lycopene concentration not reported | 51 wk, during and after carcinogen treatment | 20 | Not reported | Not reported | Prostate cancer–specific survival | NS |
| 10% tomato powder–supplemented diet vs. control | Tomato powder solids,7 lycopene concentration not reported | 20 | Not reported | Not reported | Increased survival (P = 0.026) | ||||
| 10% tomato paste + 2% FruHis supplemented diet vs. control | Tomato paste solids,6 lycopene concentration not reported | 20 | Not reported | Not reported | Increased survival (P = 0.004) | ||||
| Canene-Adams (2013) (54) | Rat, F344, PhIP | 10% tomato + 10% broccoli powder supplemented diet vs. control | Tomato and broccoli powder,8 lycopene concentration not reported | 52 wk after carcinogen treatment | 16 | Not reported | Not reported | Survival, neoplastic lesion incidence, lesion area | Increased survival (93.8% vs. 50%, P = 0.004), no effect on total lesion incidence, decreased lesion incidence in surviving rats (1.0 vs. 2.5, P = 0.017), decreased lesion area (reduced by approx. 85%, P = 0.016), all compared to PhIP-alone treatment |
Results are presented in comparison with the control group unless otherwise noted. Lycopene was not detected in control-fed animals in any study in which lycopene was measured in tissues or blood. Values are mean ± SD. DMAB, 3,2′-dimethyl-4-amino-biphenyl; FruHis, fructose-histidine; NMU, N-methyl-N-nitrosourea; NS, not significant; PhIP, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine; PIN, prostatic intraepithelial neoplasia.
Manufactured by Beer-Sheva.
Full study design included crossover with diet restriction not presented here.
Manufactured by Hoffman-La Roche.
Manufactured by Armour Foods.
Manufactured by The Morning Star Packing Co.
Manufactured by TRANSA, Henry Broch & Co.
FutureCeuticals.
TABLE 3.
Effects of tomato or lycopene feeding, with or without other dietary components, compared with control on cancer outcomes in genetically engineered mouse models of prostate carcinogenesis, listed in chronological order1
| Study | Animal model | Feeding intervention | Tomato or lycopene source, mg lycopene/kg diet | Intervention timing | Group size, n | Plasma lycopene1, μmol/L | Tissue lycopene, nmol/g | Cancer outcome measured | Cancer outcome results |
|---|---|---|---|---|---|---|---|---|---|
| Venkateswaran (2004) (57) | Mouse, Lady | Lycopene + vitamin E + selenium supplemented diets vs. control | Not reported | 30 wk | 19 | Not reported | Not reported | Prostate cancer incidence | Decreased incidence (74% vs. 11%) |
| Venkateswaran (2009) (58) | Mouse, Lady | Lycopene + vitamin E + selenium vs. control | Not reported | 22 wk | 11 | Not reported | Not reported | Prostate tumor incidence/liver metastasis | NS |
| Lycopene + vitamin E + selenium vs. control | Not reported | 38 wk | 10 | Not reported | Not reported | Prostate tumor incidence/liver metastasis | NS incidence; decreased metastasis (P < 0.05) | ||
| Lycopene + vitamin E + selenium vs. control | Not reported | 50 wk | 13 | Not reported | Not reported | Prostate tumor incidence/liver metastasis | Decreased incidence (8% vs 77% tumor-free; P < 0.0001); decreased metastasis (P < 0.0001) | ||
| Lycopene + vitamin E + selenium vs. control | Not reported | 54 wk | 10 | Not reported | Not reported | Prostate tumor incidence/liver metastasis | Decreased incidence (8% vs 90% tumor-free; P < 0.0001); decreased metastasis (P < 0.0001) | ||
| Konijeti (2010) (35) | Mouse, TRAMP × C57Bl/6 | Tomato paste–supplemented diet vs. control | Tomato paste,2 28 mg lycopene/kg diet | 16 wk | 20 | Not reported | Not reported | Prostate tumor incidence | NS |
| Lycopene beadlet–supplemented diet vs. control | Lycopene beadlets,3 28 mg lycopene/kg diet | 16 wk | 20 | Not reported | Not reported | Prostate tumor incidence | Decreased incidence (95% vs. 60%; P < 0.00197) | ||
| Pannellini (2010) (55) | Mouse, TRAMP × C57Bl/6 | 10% tomato paste–supplemented diet vs. control | Spray-dried tomato powder,4 131.5 mg lycopene/kg diet | 7 wk (terminated at 12 wk old) | 5 | Not reported | Not reported | Percentage area of prostate with PIN or adenocarcinoma | Decreased PIN area (P < 0.01) and increased normal area (P < 0.01) |
| 10% tomato paste–supplemented diet vs. control | Spray-dried tomato powder,4 131.5 mg lycopene/kg diet | 15 wk (terminated at 20 wk old) | 5 | 0.15 | Not reported | Percentage area of prostate with PIN or adenocarcinoma | Decreased adenocarcinoma (64% vs. 3%; P < 0.01) and increased normal area (P < 0.01) | ||
| 10% tomato paste–supplemented diet vs. control | Spray-dried tomato powder,4 131.5 mg lycopene/kg diet | 20 wk (terminated at 25 wk old) | 5 | 0.12 | Not reported | Percentage area of prostate with PIN or adenocarcinoma | Decreased adenocarcinoma (79% vs. 10%; P < 0.01), increased PIN (P < 0.01) and increased normal area (P < 0.01) | ||
| 10% tomato paste–supplemented diet vs. control | Spray-dried tomato powder,4 131.5 mg lycopene/kg diet | 25 wk (terminated at 30 wk old) | 5 | 0.1 | Not reported | -- | -- | ||
| 10% tomato paste–supplemented diet vs. control | Spray-dried tomato powder,4 131.5 mg lycopene/kg diet | 28 wk (terminated at 33 wk old) | 5 | 0.09 | Not reported | Prostate cancer specific–survival | Increased survival (67% vs. 11%) | ||
| Zuniga (2013) (66) | Mouse, TRAMP C57Bl/6 × FVB F1 | 10% tomato powder–supplemented diet vs. control | Tomato powder,5 268 mg lycopene/kg diet | 14 wk | 31 | 0.67 ± 0.16 | Liver: 4.56 ± 2.41Prostate: 0.25 ± 0.1Tumor: 1.42 ± 0.59 | Incidence of prostate cancer | Decreased incidence (100% vs. 61%; P < 0.001) |
| 10% tomato powder + 2% soy germ supplemented diet vs. control | Tomato powder,5 268 mg lycopene/kg diet | 14 wk | 27 | 0.44 ± 0.09 | Liver: 3.14 ± 1.48Prostate: 0.18 ± 0.08Tumor: 0.47 ± 0.25 | Incidence of prostate cancer | Decreased incidence (100% vs. 45%; P < 0.001) | ||
| Conlon (2015) (74) | Mouse, TRAMP C57Bl/6 × FVB F1 | 10% tomato powder–supplemented diet vs. control | Tomato powder,5 13 mg lycopene/kg diet | 4 wk (terminated at 12 wk old) | 59 | 0.47 ± 0.07 | Liver: 1.4 ± 0.2Prostate: 0.4 ± 0.2 | Lesion incidence, lesion severity | NS incidence; NS severity |
| 10% tomato powder–supplemented diet vs. control | Tomato powder,5 13 mg lycopene/kg diet | 8 wk (terminated at 16 wk old) | 60 | 0.81 ± 0.18 | Liver: 2.4 ± 0.5Prostate: 0.4 ± 0.1 | Lesion incidence, lesion severity | NS incidence; greater incidence of PIN (43.3% vs. 76.7%; P = 0.014) and lower incidence of poorly differentiated adenocarcinoma (0% vs. 16.7%; P = 0.024) compared with control-fed | ||
| 10% tomato powder–supplemented diet vs. control | Tomato powder,5 13 mg lycopene/kg diet | 12 wk (terminated at 20 wk old) | 59 | 0.66 ± 0.15 | Liver: 1.9 ± 0.3Prostate: 0.4 ± 0.1 | Lesion incidence, lesion severity | NS incidence; NS severity | ||
| Tan (2017) (36) | Mouse, TRAMP C57Bl/6 × Bco2+/+ | 10% tomato powder–supplemented diet vs. control | Tomato powder,5 384 mg lycopene/kg diet | 15 wk (terminated at 18 wk old) | 39–46 | 0.245 ± 0.013 | Not reported | Lesion incidence, lesion severity | Decreased incidence (15.9% vs 80.4%; P < 0.0001); decreased severity (P < 0.0001) |
| Lycopene beadlet–supplemented diet vs. control | Lycopene beadlets,3 462 mg lycopene/kg diet | 15 wk (terminated at 18 wk old) | 39–46 | 0.252 ± 0.009 | Not reported | Lesion incidence, lesion severity | Decreased incidence (11.1% vs. 80.4%; P < 0.0001); decreased severity (P < 0.0001) | ||
| Mouse, TRAMP C57Bl/6 × Bco2-/- | 10% tomato powder–supplemented diet vs. control | Tomato powder,5 384 mg lycopene/kg diet | 15 wk (terminated at 18 wk old) | 39–46 | 0.387 ± 0.051 | Not reported | Lesion incidence, lesion severity | Decreased incidence (30.2% vs 67.5%; P = 0.0004); decreased severity (P = 0.0002) | |
| Lycopene beadlet–supplemented diet vs. control | Lycopene beadlets3 462 mg lycopene/kg diet | 15 wk (terminated at 18 wk old) | 39–46 | 0.404 ± 0.051 | Not reported | Lesion incidence, lesion severity | NS incidence; NS severity | ||
| Rowles (2020) (56) | Mouse, TRAMP C57Bl/6, castrate-resistant tumor model | 10% powdered tomato paste–supplemented diet | Powdered tomato paste,6 21 mg lycopene/kg diet | Initiated at 4 wk of age, duration 14–26 wk, depending on detection of tumor by ultrasound | 26 | 0.569 ± 0.098 | Liver: 15.7 ± 2.1Prostate: 0.38 ± 0.09Tumor: 0.09 ± 0.01 | Lesion incidence, time to tumor detection, final tumor weight | NS incidence; NS time to detection, NS final tumor weight |
| Initiated at 12 wk of age, duration 6–18 wk, depending on detection of tumor by ultrasound | 28 | 0.551 ± 0.097 | Liver: 17.4 ± 2.1Prostate: 0.37 ± 0.04Tumor: 0.12 ± 0.02 | NS incidence; NS time to detection, NS final tumor weight | |||||
| Mouse, TRAMP C57Bl/6, castrate-resistant carcinogenesis model | 10% powdered tomato paste–supplemented diet | Powdered tomato paste,6 21 mg lycopene/kg diet | Initiated at 12 wk of age, duration 6–18 wk, depending on detection of tumor by ultrasound | 29 | 0.285 ± 0.022 | Liver: 10.1 ± 0.5Prostate: 1.50Tumor: 0.07 ± 0.03 | Lesion incidence, time to tumor detection, final tumor weight | NS incidence; NS time to detection, NS final tumor weight | |
| Lycopene beadlet–supplemented diet | Lycopene beadlets,3 73 mg lycopene/kg diet | Initiated at 12 wk of age, duration 6–18 wk, depending on detection of tumor by ultrasound | 27 | 0.346 ± 0.035 | Liver: 8.5 ± 1.1 Prostate: 0.68Tumor: 0.10 ± 0.03 | NS incidence; NS time to detection, NS final tumor weight |
Results are presented in comparison with the control group unless otherwise noted. Lycopene was not detected in control-fed animals in any study in which lycopene was measured in tissues or blood. Values are mean ± SD. Bco, β-carotene oxygenase; NS, not significant; PIN, prostatic intraepithelial neoplasia; TRAMP, transgenic adenocarcinoma of the mouse prostate.
Manufactured by Campbell's Soup Company.
Manufactured by DSM.
Processed in-house.
Manufactured by FutureCeuticals.
Contadina, Del Monte Foods.
Carcinogenesis Models
The impacts of tomato and lycopene feeding on chemically induced prostate carcinogenesis
Initial studies examining the impact of lycopene or tomato feeding on prostate carcinogenesis utilized several rat models of chemically induced carcinogenesis (Table 2) (33, 48). The carcinogens employed induce specific types of DNA changes such that the combination of androgens with the nitro-compound NMU causes guanine nucleotide methylation, the polycyclic aromatic hydrocarbon 3,2′-dimethyl-4-amino-biphenyl (DMAB) causes transversion of nucleotides, and the heterocyclic amine 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) causes DNA adduct formation. These DNA changes cause genomic damage that initiates a cascade leading to the development of adenocarcinomas of the ventral or dorsolateral prostate, in addition to other tissue sites (49, 50). Currently our knowledge regarding environmental carcinogens that might impact human prostate carcinogenesis is poor, thus the direct relevance of these compounds is uncertain, yet the DNA damage caused by these agents reflects processes common to many carcinogens. The histopathological progression of cancer in these models corresponds with the progression observed in human disease (51). Using these models, the effects of timing of lycopene feeding, of combining tomato and broccoli feeding, of tomato powder compared with lycopene alone, and of FruHis in tomato products on rodent prostate carcinogenesis have been examined.
Timing and duration of tomato or lycopene feeding
The importance of the timing of lycopene feeding, relative to the carcinogen exposure, rodent age, and duration of the feeding intervention, was first suggested by studies of DMAB-induced prostate carcinogenesis in rats (Table 2) (48). Feeding lycopene for 40 wk after the completion of a 20-wk DMAB treatment significantly decreased PIN and carcinoma incidence, whereas feeding lycopene during only the 20-wk DMAB exposure did not significantly decrease carcinoma and PIN incidence. In a follow-up dose–response experiment (0, 5, 15, and 45 mg/kg diet) with lycopene (48), carcinoma incidence nonsignificantly decreased from 34% to 17.6%, 17.6%, and 10.5%, respectively (Table 2). The serum lycopene concentrations ranging from <0.019 to 0.037 μmol/L in rats fed 5–45 mg/kg diet in this study (48) were well below those typically observed in large, epidemiological studies of Americans (20, 21, 52). Indeed, later rodent studies demonstrated protective effects at ≥10-fold blood lycopene concentrations than those achieved in this report (Table 2), and lower blood lycopene concentrations in humans are also ∼10-fold greater than those achieved in this study (53). Another experiment within the same report indicated that a higher dose of lycopene (45 mg/kg diet) provided for 50 wk after a 10-wk treatment with another carcinogen, PhIP, did not reduce neoplastic lesion incidence in rats (48).
Direct comparison of tomato components and lycopene
Several studies directly compared tomato powder with lycopene feeding in prostate carcinogenesis models. In an NMU-testosterone-induced rat carcinogenesis model (33), tomato powder feeding was more effective than lycopene alone in prolonging survival, despite >90% lower dietary concentrations of lycopene in the tomato powder and similar blood lycopene concentrations between the tomato- and lycopene-fed groups (Table 2) (33). This finding raised the hypothesis that the mixture of phytochemicals in tomato powder was more effective than lycopene alone in inhibiting NMU-induced rat prostate carcinogenesis. This hypothesis led to several subsequent studies using other rodent models to compare the effects of whole tomato food products or phytochemical-nutrient combinations. For example, studies examined the impact of a hypothesized anticancer bioactive compound present in some processed tomato products called FruHis, a ketosamine carbohydrate derivative (product of fructose + histidine) (40). The investigators examined testosterone- and NMU-induced carcinogenesis in rats fed either a control diet, 10% tomato paste (very low in FruHis), 10% tomato powder (naturally containing FruHis), or 10% tomato paste plus 2% FruHis, starting 4 wk prior to NMU treatment (Table 2). Survival rates significantly increased with feeding either tomato powder or tomato paste + FruHis compared with control, whereas tomato paste alone nonsignificantly increased survival. The tomato paste + FruHis group had the fewest macroscopic prostate tumor–bearing rats. Together, these findings suggest that FruHis could be an active, anticancer component in processed tomato products worthy of additional investigation.
Tomato combined with other foods
A study in the PhIP model of rat carcinogenesis in which rats were fed either a combination of tomato (10% w/w) and broccoli (10% w/w) powder (dietary lycopene concentrations not reported) (Table 2) or control diet found that the combination diet reduced incidence of ventral prostate cribriform PIN and carcinoma in situ at 52 wk (54). Although this and the previously mentioned PhIP study (48, 54) cannot be directly compared because there was neither a tomato-only treatment nor quantitation of the lycopene provided by the tomato diet, it is possible that the tomato powder in the latter study provided a greater lycopene dose, or that the combination of tomato and broccoli was critical for significant anticarcinogenic bioactivity in this model.
Summary of the impacts of tomato and lycopene feeding on chemically induced prostate carcinogenesis
In summary, rat studies of chemically induced carcinogenesis are very few, but suggest that lycopene and tomato components provided alone or in combination with broccoli powder or with FruHis can inhibit prostate carcinogenesis. The limited number of investigations prevents conclusions regarding specific mechanisms. Studies in these models suggest that whole tomato exposure, providing a larger array of bioactive compounds, could be slightly more impactful than lycopene alone. The potential of tomato components to impact chemical carcinogenesis at the level of carcinogen metabolism, both activation and detoxification, and cellular DNA repair, has not been adequately illuminated.
The impact of lycopene, tomato, and combination treatments on GEM models of prostate carcinogenesis
Mice genetically engineered to carry the early region of the ectopic polyomavirus simian virus 40 (SV40) oncogene and express the large T antigen (Tag) and/or the small T antigen in the prostate (Table 1) have been used in a number of studies to investigate the effects of lycopene, tomato, and other agents in prostate carcinogenesis (Table 3). The Tag binds and inhibits the tumor suppressors, transformation related protein 53 (TRP53) and RB transcriptional corepressor 1 (RB1), as well as a number of other proteins involved in transformation, resulting in the TRAMP and Lady models, respectively. Both GEMs utilize SV40 to model a number of oncogenic processes resulting from genetic damage [reviewed by Grabowska et al. (27)], with SV40 expression being controlled by androgen-responsive small probasin promoter in the Lady model and by the large probasin promoter in the TRAMP model. The TRAMP model, in particular, has been used widely because of its high penetrance, well-characterized progression of time from hyperplasia to intraepithelial neoplasia, invasive carcinoma, and, ultimately metastatic progression (27). With time, the lesions evolve in TRAMP × FVB (Friend Virus B) mice to demonstrate a high incidence of poorly differentiated carcinoma with neuroendocrine features, a phenotype primarily seen in more advanced, castrate-resistant prostate cancer in humans. Mouse genetic background impacts the cancer cascade, with TRAMP × C57Bl/6 mice showing a slower rate of progression to cancers with neuroendocrine features than FVB background mice (27).
Whole tomato product compared with lycopene
Following an earlier rat chemical carcinogenesis study showing that tomato powder was slightly more efficacious than lycopene (33), the TRAMP mouse model was used to assess the anticancer effect of tomato compared with lycopene (35). In contrast to the rat study (33), in TRAMP × C57Bl/6 mice, lycopene beadlet supplementation (28 mg/kg diet) from 4 to 20 wk of age significantly reduced cancer incidence, whereas lycopene-matched tomato paste (28 mg/kg diet) feeding did not (35). Interestingly, serum and prostate lycopene concentrations assessed in nontransgenic littermates fed for 3 wk did not differ between tomato paste and lycopene beadlet feeding; thus, the different bioactivities of the diets are not clearly explained by lycopene exposure differences. Thus, such a finding suggests that other components in the tomato could have counteracted the benefits of lycopene, a finding not supported by other studies. In comparison, when fed a higher lycopene-containing 10% tomato powder diet (providing 132 mg lycopene/kg diet), the TRAMP × C57Bl/6 model showed greater overall survival and lower rates of metastasis compared with controls (55). In a follow-up, 33-wk-long time-course study in this model, tomato powder feeding resulted in a greater area of normal prostate histology at 12 and 25 wk of age compared with feeding a control diet (Table 2) (55). In a third study, our group reported that tomato powder (384 mg lycopene/kg diet) or lycopene supplementation (462 mg lycopene/kg diet) similarly reduced prostate cancer incidence in the TRAMP × C57Bl/6 model at 18 wk of age compared with control feeding (36). Overall, tomato powder feeding improved survival and reduced incidence in 2 androgen-sensitive TRAMP studies (36, 55), whereas tomato paste neither reduced cancer incidence in another androgen-sensitive (35) nor in a castrate-resistant prostate carcinogenesis study (56). Differing results for the effect of tomato and lycopene on TRAMP carcinogenesis observed in the aforementioned studies (35, 36, 55) might be due to differences in the study duration and outcomes measured, variation in the dose of lycopene delivered, and differences in phytochemical patterns provided among various tomato preparations (40).
Lycopene combined with nutrients and the effect of intervention timing
The first study to utilize a GEM model to study the effects of lycopene on prostate carcinogenesis examined a combination of nutrients and lycopene: vitamin E (α-tocopherol succinate; “800 IU/d human equivalent”), selenium (seleno-dl-methionine; “200 μg/d human equivalent”), and lycopene (“50 mg/d human equivalent”) in the Lady (12T-10, the slowest progressing Lady line) model (57). Unfortunately, the dosing is reported in terms of “human equivalents” per day, the scaling methodology is not reported, nor was serum or tissue lycopene measured, making it impossible for readers to compare the intervention with human exposures or with other preclinical rodent studies. Mice fed the nutrient and lycopene mixture starting at 4–5 wk until 28–32 wk of age showed significantly lower cancer incidence compared with those fed the control diet. In a follow-up study (58), the impact of the timing and duration of the antioxidant mixture feeding on Lady (12T-10) prostate carcinogenesis was assessed. The Lady 12T-10 model slowly progresses from high grade prostatic intraepithelial neoplasia (HGPIN), to invasive neuroendocrine carcinoma, and then to metastasis [reviewed by Grabowska et al. (27)]. Whereas the combination of vitamin E and selenium did not reduce cancer incidence compared with the control group, regardless of feeding duration, the addition of lycopene to vitamin E and selenium reduced cancer incidence over the 58-wk study in mice that were fed the mixture starting early in life (4 and 8 wk of age), but not with the later introduction (20 and 36 wk of age). In both experiments, transgene expression was intact in control and lycopene-fed mice (57, 58), and serum testosterone concentrations were verified to be unchanged in the earlier study (57), indicating that the feeding regimen itself did not indirectly reduce cancer incidence by reducing Tag expression. Interestingly, incidence of liver metastases was reduced with combined lycopene, selenium, and vitamin E feeding when initiated at 4, 8, and 20 wk of age (58). Key findings from these experiments are that a combination of nutrients and lycopene was protective against prostate carcinogenesis and that longer exposures, beginning earlier in carcinogenesis, were more effective in reducing total tumor incidence and metastasis (58), which is similar to findings from a study providing lycopene alone to TRAMP mice (36). In the context of human epidemiological data the findings are interesting, because a meta-analysis of 15 human studies indicated that although lycopene is not protective against overall prostate cancer risk, it is associated with a reduced risk of aggressive and advanced cancers (59), which could be consistent with the prevention of the more aggressive, metastatic phenotypes of the Lady model. Based upon the few studies conducted in GEM of prostate cancer, it appears that tomato powder and lycopene demonstrate similar anticancer activity (36, 55). Furthermore, this effect occurs with blood lycopene concentrations that are similar to the lower to average concentrations in humans (median plasma lycopene = 0.44 μmol/L; lower quartile = 0 to <0.29 μmol/L) (53) (likely due to lower absorption of intact lycopene in rodents).
The effect of intervention timing and duration was tested using the TRAMP C57Bl/6 × FVB F1 model. When compared with initiating feeding of a lower-lycopene tomato powder (13 mg lycopene/kg diet) at weaning (4 wk of age) compared with at 8 wk of age, the delayed initiation of feeding attenuated the effect of tomato feeding on TRAMP C57Bl/6 × FVB F1 carcinogenesis. Whereas the later initiation of tomato feeding shifted the histopathology to a lower proportion of poorly differentiated adenocarcinoma and greater proportion of PIN at 16 wk, there was no difference in overall cancer incidence at 12, 16, or 20 wk (74) compared with control. Interestingly, despite providing 95% lower amounts of lycopene in this tomato powder than in a previous study of tomato powder and soy germ feeding in TRAMP mice (66), the achieved serum lycopene concentrations were similar, suggesting that feeding duration and timing was a critical determinant of the diet's efficacy.
Tomato combined with other foods
The impact of soy combined with tomato powder was examined in the TRAMP model based upon human epidemiology (62) and the potential impact of soy bioactive compounds previously observed in in vitro (63) and rodent models (64, 65). Prostate carcinogenesis was significantly inhibited in the TRAMP C57Bl/6 × FVB1 F1 model, a model with a more aggressive phenotype, at 18 wk of age when fed tomato powder (268 mg lycopene/kg diet), bioactive compound–rich 2% soy germ, and a combination of both from 4 wk of age, when compared with control feeding (66). The lowest incidence was in the combination tomato and soy germ group, despite slightly lower serum lycopene concentrations in the tomato + soy (0.44 ± 0.04 μmol/L) compared with the tomato-alone (0.67 ± 0.07 μmol/L) (P < 0.05) groups. Based upon these findings, fully characterized food products are being developed and tested in human phase I/II studies (19, 21).
Impact of host genetics
A number of polymorphisms in the β-carotene oxygenase (BCO) genes in humans, as well as other genes involved in carotenoid assimilation, might contribute to variability in pharmacokinetic and therapeutic/preventive responses to dietary carotenoids (reviewed in references 67 and 68). Particularly relevant to lycopene metabolism are the 2 mammalian enzymes known to metabolize carotenoids, BCO1 and BCO2, which cleave carotenoids centrally and eccentrically, respectively, to result in the clearance of intact carotenoids and generation of potentially bioactive carotenoid metabolites (69–71). We and others have previously proposed that metabolites of lycopene (lycopenoids) could be responsible for lycopene's reported anticarcinogenic bioactivity (72, 73). To this end, the effect of lycopene and tomato powder feeding was modestly attenuated in TRAMP × C57Bl/6 mice lacking Bco2 expression, with Bco2–/– mice fed lycopene having slightly greater rates of adenocarcinoma than Bco2+/+ mice fed lycopene (36). This difference by Bco2 genotype was despite 50% greater serum lycopene concentrations in Bco2–/– compared with Bco2+/+ mice, suggesting that the anticancer activity of lycopene feeding can be impacted by BCO2 activity, and potential generation of bioactive lycopene cleavage metabolites.
Impact on castrate-resistant prostate cancer
Most recently, we observed that castrate-resistant prostate cancer was not inhibited by either lyophilized tomato paste (21 mg lycopene/kg diet) or lycopene (73 mg lycopene/kg diet) when feeding was initiated following castration at 12 wk of age (56). This key finding could be due in part to the later initiation and shorter duration of feeding (starting after castration at 12 wk of age rather than weaning) or perhaps due to lower lycopene exposures than the other androgen-sensitive TRAMP studies (36, 55). It is a critical finding that castrate-resistant cancer progression appears to be unresponsive to tomato or lycopene intake. Although, only a single study, this report supports the hypothesis that androgen signaling of prostate carcinogenesis is the target of tomato/lycopene (39, 56, 60, 61). Indeed, this work strongly suggests that future translation to human studies should focus on early steps in prostate cancer and that prostate cancer patients with emerging castrate-resistant disease should focus on evidence-based therapies and not tomato components as often marketed by purveyors of alternative therapy. Additional dose–response studies focusing upon specific phases of TRAMP carcinogenesis are needed to inform future research in humans.
Summary of studies in GEM models
Overall, the studies using TRAMP (androgen-driven SV40 GEM) models suggest that tomato and lycopene provided for a lifelong duration can delay the carcinogenesis cascade that is driven by disruption of normal TRP53 and RB function. In a recent study, these beneficial effects are lost in the transition to castrate-resistant disease. Although more work is necessary, the hypothesis that lycopene and/or other tomato phytochemicals act via inhibition of androgen stimulation of prostate carcinogenesis is supported by the evidence. The studies suggest the potential of tomato components to enhance the benefits of other dietary factors, nutrients, or chemopreventive agents for a greater therapeutic index and, perhaps, additive or synergistic effects, yet few combinations have been examined in well-designed preclinical models. The rapid growth in development of new GEM models of prostate carcinogenesis provides many opportunities to further dissect mechanisms of action and provide much greater insight into critical dose–response relations.
Transplantable Tumorigenesis Models
The effects of tomato or lycopene supplementation, along with other agents, have been tested in a number of rat and mouse implantable tumor models. The studies have conveyed additional information regarding dose–response relations, potential mechanisms of action, and the critical role of hormone and nutrient metabolism.
Effects of tomato and lycopene on Dunning tumorigenesis in rats
The slow-growing, androgen-sensitive R3327-H Dunning rat prostate cancer cell line and its faster-growing metastatic subline, MAT-LyLu (capable of metastasizing to the lymph nodes and lungs) [reviewed by Tennant et al. (75)] have been investigated in 3 studies with lycopene or tomato along with other dietary components.
Lycopene combined with selenium and γ-tocopherol
The effects of lycopene (200 mg lycopene/kg diet), vitamin E (540 mg/kg diet; dl-α-tocopheryl acetate), or the combination on the growth of orthotopically injected MAT-LyLu cells in the Copenhagen rat ventral prostate were examined over 18 d (61) and showed no significant impact on tumor weight at necropsy (Table 4). A second study in the Dunning R3327-H model (76) assessed the individual contribution of lycopene and the combined effect of vitamin E (200 mg/kg diet; γ-tocopherol), lycopene (250 mg/kg diet), and/or selenium (1 mg/kg diet; methylselenocysteine). Lycopene alone or in combination with vitamin E and selenium did not significantly decrease final tumor volume or final tumor weight.
TABLE 4.
Effects of tomato or lycopene feeding, with or without other dietary components, on cancer outcomes in rat and mouse tumorigenesis models, in chronological order of publication1
| Study | Animal model | Feeding intervention | Source, mg lycopene/kg diet or body weight | Intervention duration, wk | Group size, n | Plasma lycopene, μmol/L | Tissue lycopene, nmol/g | Cancer outcome measured | Cancer outcome results |
|---|---|---|---|---|---|---|---|---|---|
| Siler (2004) (61) | Rat, Copenhagen, Dunning MatLyLu orthotopic injection | Lycopene beadlet–supplemented diet | Lycopene beadlets,2 200 mg lycopene/kg diet | 4, prior to injection | 6 | 1.02 ± 0.30 | Not reported | Not applicable | Not applicable |
| Lycopene + vitamin E supplemented diet | Lycopene beadlets,2 200 mg lycopene/kg diet | 4, prior to injection | 6 | 0.92 ± 0.22 | Not reported | Not applicable | Not applicable | ||
| Lycopene beadlet–supplemented diet | Lycopene beadlets,2 200 mg lycopene/kg diet | 4, prior to injection + 2.5 after injection | 6 | 0.004 ± 0.01 | Prostate tumor: 0.38 ± 0.11 | Tumor volume 14 d postinjection and tumor weight 18 d postinjection | NS | ||
| Lycopene + vitamin E supplemented diet | Lycopene beadlets,2 200 mg lycopene/kg diet | 4, prior to injection + 2.5 after injection | 6 | 0.051 ± 0.068 | Prostate tumor: 0.42 ± 0.18 | Tumor volume 14 d postinjection and tumor weight 18 d postinjection | NS | ||
| Tang (2005) (78) | Mouse, BALB/c nude, DU145 | Lycopene oral gavage | Lycopene isolated from tomatoes, 10 mg/kg BW (5× weekly) | 8 | 15 | Not reported | Not reported | Tumor volume; tumor weight | NS; NS (49% lower) |
| Lycopene oral gavage | Lycopene isolated from tomatoes, 100 mg/kg BW (5× weekly) | 8 | 15 | Not reported | Not reported | Tumor volume; tumor weight | Decreased volume (∼50% lower, P < 0.05); decreased weight (56% less; P < 0.05) | ||
| Lycopene oral gavage | Lycopene isolated from tomatoes, 300 mg/kg BW (5× weekly) | 8 | 15 | Not reported | Not reported | Tumor volume; tumor weight | Decreased volume (∼80% lower, P < 0.01); decreased weight (76% less; P < 0.01) | ||
| Limpens (2006) (77) | Mouse, NMRI nu/nu, PC-346C orthotopic | Lycopene, orally dosed | LycoVit 10% beadlets,3 5 mg lycopene/kg BW (daily) | 6 | 6–9 | Not reported | Liver: 0.069 ± 0.036; prostate tumor: 0.014 ± .011 | Tumor volume; survival | NS (53% decrease in volume); NS (19% increased survival) |
| Lycopene, orally dosed | LycoVit 10% beadlets,3 50 mg lycopene/kg BW (daily) | 6 | 6–9 | Not reported | Liver: 0.321 ± 0.294; prostate tumor: 0.038 ± 0.015 | Tumor volume; survival | NS | ||
| Lycopene + vitamin E, orally dosed | LycoVit 10% beadlets,3 5 mg lycopene/kg BW (daily) | 6 | 6–9 | Not reported | Liver: 0.058 ± 0.013; prostate tumor: 0.012 ± 0.005 | Tumor volume; survival | Decreased tumor volume (73% lower, P < 0.05); increased survival (40% longer, P < 0.05) | ||
| Canene-Adams (2007) (34) | Rat, Copenhagen; Dunning R3327-H | 10% tomato powder–supplemented diet | Tomato powder,4 7 mg lycopene/kg diet | 22 | 27 | 0.511 ± 0.041 | Liver: 189 ± 15; prostate: 0.5 ± 0.06; tumor: 0.4 ± 0.03 | Tumor weight | NS (33% lower tumor weight) |
| 5% tomato powder + 5% broccoli powder supplemented diet | Tomato powder,4 3 mg lycopene/kg diet | 22 | 24 | 0.439 ± 0.048 | Liver: 123 ± 14; prostate: 0.3 ± 0.01; tumor: 0.26 ± 0.03 | Tumor weight | NS (30% lower tumor weight) | ||
| 10% tomato powder + 10% broccoli powder supplemented diet | Tomato powder,4 6 mg lycopene/kg diet | 22 | 26 | 0.538 ± 0.039 | Liver: 160 ± 9; prostate: 0.4 ± 0.02; tumor: 0.42 ± 0.03 | Tumor weight | Decreased tumor weight (52% lower; P = 0.05) | ||
| Lycopene beadlet–supplemented diet | Lycopene beadlets,2 12 mg lycopene/kg diet | 22 | 23 | 0.252 ± 0.028 | Liver: 58 ± 4; prostate: 0.1 ± 0.01; tumor: 0.13 ± 0.01 | Tumor weight | NS (7% lower tumor weight) | ||
| Lycopene beadlet–supplemented diet | Lycopene beadlets,2 120 mg lycopene/kg diet | 22 | 27 | 0.884 ± 0.080 | Liver: 527 ± 40; prostate: 0.9 ± 0.08; tumor: 0.58 ± 0.03 | Tumor weight | NS (18% lower tumor weight) | ||
| Lindshield (2010) (76) | Rat, Copenhagen; Dunning R3327-H | Lycopene beadlet–supplemented diet | Lycopene beadlets,2 291 mg lycopene/kg diet | 24 | 15 | Not reported | Liver: 276 ± 91 | Tumor weight and tumor area | NS |
| Lycopene beadlet + vitamin E supplemented diet | Lycopene beadlets,2 291 mg lycopene/kg diet | 24 | 15 | Not reported | Liver: 378 ± 59 | Tumor weight and tumor area | NS | ||
| Lycopene beadlet + selenium supplemented diet | Lycopene beadlets,2 291 mg lycopene/kg diet | 24 | 15 | Not reported | Liver: 319 ± 41 | Tumor weight and tumor area | NS | ||
| Lycopene beadlet + vitamin E + selenium supplemented diet | Lycopene beadlets,2 291 mg lycopene/kg diet | 24 | 15 | Not reported | Liver: 278 ± 60 | Tumor weight and tumor area | NS | ||
| Tang (2011) (79) | Mouse, NCR-nu/nu, DU145 | Lycopene oral gavage | LycoVit 10% CWD,3 15 mg/kg BW daily | 3.5 | Not reported | Not reported | Not reported | Tumor weight, tumor volume | NS, NS |
| Lycopene oral gavage + docetaxel (10 mg/kg/wk) | LycoVit 10% CWD,3 15 mg/kg BW daily | 3.5 | Not reported | Not reported | Not reported | Tumor weight, tumor volume | Decreased weight (38% lower than docetaxel alone; P = 0.042); decreased volume (∼85%, P < 0.05) | ||
| Lycopene oral gavage | LycoVit 10% CWD,3 15 mg/kg BW daily | From 4.5 to 8.5 wk | Not reported | Not reported | Not reported | Time for tumor to reach 1500 mm3 | NS | ||
| Lycopene oral gavage + docetaxel (5mg/kg) | LycoVit 10% CWD,3 15 mg/kg BW daily | From 4.5 to 8.5 wk | Not reported | Not reported | Not reported | Time for tumor to reach 1500 mm3 | Increased time to 64 d vs. control time of 41 d (P < 0.001) | ||
| Lycopene oral gavage + docetaxel (10 mg/kg) | LycoVit 10% CWD,3 15 mg/kg BW daily | From 4.5 to 8.5 wk | Not reported | Not reported | Not reported | Time for tumor to reach 1500 mm3 | Increased time to 70 d vs. control time of 41 d (P < 0.001) | ||
| Yang (2011) (80) | Mouse, BALB/c nude, PC-3 | Lycopene in corn oil, oral | Lycopene,5 4 mg/kg BW (2×/wk) | 7 | 6 | Not detected | Not reported | Tumor volume; tumor weight 7 wk postimplantation | Decreased volume (∼40%, P < 0.001); decreased weight (∼30%; P < 0.05) |
| Lycopene,5 16 mg/kg BW (2×/wk) | 7 | 6 | 0.118 ± 0.056 | Not reported | Tumor volume; tumor weight 7 wk postimplantation | Decreased volume (67% lower; P < 0.001); decreased weight (∼65%, P < 0.001) | |||
| Kolberg (2015) (81) | Mouse, NMRI nude | 10% tomato paste in diet | Tomato paste,6 30.9 mg lycopene/kg diet or 2.6 mg/kg BW | 1 wk prefeeding + 5 wk postimplantation | 15 | 0.31 ± 0.14 | Liver: 2.13 ± 1.06; tumor: 0.08 ± 0.05 | Tumor volume 5 wk postimplantation | NS |
| Jiang (2018) (82) | Mouse, BALB/c nude, PC-3 | Lycopene gavage | Lycopene,5 1 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 67 d to 84 d (P < 0.001); decreased volume (∼8% less than control; P < 0.01) |
| Lycopene gavage | Lycopene,5 5 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 67 d to 105 d (P < 0.001); decreased volume (∼20% less than control; P < 0.01) | ||
| Lycopene gavage | Lycopene,5 10 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 67 d to 120 d (P < 0.001); decreased volume (∼35% less than control; P < 0.01) | ||
| Mouse, BALB/c nude, DU145 | Lycopene gavage | Lycopene,5 1 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 60 d to 73 d (P < 0.001); decreased volume (∼3% less than control; P < 0.01) | |
| Lycopene gavage | Lycopene,5 5 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 60 d to 87 d (P < 0.001); decreased volume (∼20% less than control; P < 0.01) | ||
| Lycopene gavage | Lycopene,5 10 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 60 d to 120 d (P < 0.001); decreased volume (∼20% less than control; P < 0.01) | ||
| Mouse, BALB/c nude, LNCaP | Lycopene gavage | Lycopene,5 1 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 67 d to 81 d (P < 0.001); decreased volume (∼20% less than control; P < 0.01) | |
| Lycopene gavage | Lycopene,5 5 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 67 d to 108 d (P < 0.001); decreased volume (∼40% less than control; P < 0.01) | ||
| Lycopene gavage | Lycopene,5 10 mg lycopene/kg BW | 1 wk after implantation, then no treatment for remainder of study | 10 | Not reported | Not reported | Survival time over 180 d, and comparison of group tumor volumes prior to first death | Increased survival time from 67 d to 135 d (P < 0.001); decreased volume (∼55% less than control; P < 0.01) |
Results are presented in comparison with the control group unless otherwise noted. Lycopene was not detected in control-fed animals in any study in which lycopene was measured in tissues or blood. Values are mean ± SD. BW, body weight; CWD, cold water dispersible; NS, not significant.
Manufactured by DSM Nutritional Products.
Manufactured by BASF.
Manufactured by Gilroy Foods.
Sold by Wako.
Purchased locally, manufacturer not provided.
Lycopene compared with tomato and tomato combined with other foods
Feeding lycopene alone (12 mg/kg diet) was found to be less effective than tomato feeding, with or without broccoli, in inhibiting tumorigenesis in the slower-growing Dunning R3327-H androgen-dependent model (34). In this study, feeding a 10% tomato powder, a 10% broccoli powder, lower or higher combinations of tomato and broccoli (5% tomato + 5% broccoli, 10% tomato + 10% broccoli), or lycopene (12 or 120 mg lycopene/kg diet), was compared with pharmacological androgen inhibition (finasteride), or surgical androgen removal (castration). The experimental diets, pharmacological, and surgical treatments were implemented beginning 4 wk before tumor cell implantation, and tumor growth was monitored up to 18 wk post tumor injection (34). The finasteride, as well as lower or higher lycopene treatments, led to nonsignificant decreases in end-of-study tumor weight by 14%, 7%, and 18%, respectively. Castration significantly decreased tumor weight to 38% that of the control (P = 0.001), followed by the combination of 10% tomato powder with 10% broccoli, which decreased tumor weight to 48% that of the control (P = 0.001), then the 10% tomato diet, which decreased tumor weights to 67% of the control (P = 0.05) (Table 4). These findings suggest that nonlycopene tomato phytochemicals could contribute to inhibition of tumor growth, disrupting the balance between proliferation and apoptotic cascades within prostate cancer cells, or indirectly by impacting the autocrine and paracrine signaling within the tumor microenvironment or hormonal environment.
Effects of tomato and lycopene on androgen-dependent and -independent human prostate cancer xenograft tumorigenesis
The effects of tomato and lycopene have been tested on a number of well-characterized androgen-sensitive and androgen-independent human prostate cancer xenograft mouse models [reviewed by Navone et al. (28)]. These models typically utilize cell lines derived from metastatic sites and are thus representative of an advanced and more aggressive phenotype.
Lycopene combined with other antioxidants and androgen-dependent xenografts
The dose-dependent effect of lycopene [5 or 50 mg lycopene/kg body weight (BW)], vitamin E [5 or 50 mg vitamin E (all-rac-α-tocopheryl acetate)/kg BW], or both (5 mg lycopene + 5 mg vitamin E/kg BW) on tumor growth was examined using the androgen-dependent PC-346C human cell line injected orthotopically into the dorsolateral prostate of NMRI nu/nu mice (77). In this study, only the combination of lycopene and vitamin E significantly decreased tumor volume, which was associated with an increase in median survival. There was also a trend toward reduction in tumor volume and increase in median survival with the 5 mg lycopene/kg BW treatment, which did not reach statistical significance, potentially in part because the study was underpowered (6–9 animals/group) given the large variability in tumor volume, which is often characteristic of xenograft models. Nonetheless, the findings suggest that lycopene alone was not a potent inhibitor of in vivo growth of this androgen-dependent human cell line, though making broad conclusions without evaluation of a variety of androgen-dependent lines would be precarious.
Lycopene and androgen-independent xenografts
The effects of lycopene on androgen-independent human prostate cell line xenografts have been evaluated in several studies. Interestingly, these studies showed effects of lycopene that have not been observed in the rodent models of castrate-resistant prostate cancer. High doses of lycopene (100 or 300 mg lycopene/kg BW provided 5 times/wk for 8 wk) reduced the growth of androgen-independent DU145 cells implanted subcutaneously in male BALB/c nude mice (78), though a lower dose of 10 mg lycopene/kg BW did not impact tumorigenesis. Interestingly, when pretreated in culture with 20 μmol/L lycopene for 5 d, the DU145 cells did not develop tumors compared with their untreated counterparts when injected into the same mouse at different sites (78). The unique features of the DU145 cell line that result in sensitivity to lycopene, compared with lack of an impact with the castrate-resistant carcinogenesis model, are unknown.
Lycopene in combination with docetaxel chemotherapy in androgen-independent xenografts
A subsequent DU145 study reported that lycopene could enhance the anticancer effects of docetaxel, a chemotherapeutic agent used commonly for the treatment of metastatic and typically castrate-resistant prostate cancer (79). NCR-nu/nu mice were injected subcutaneously on the flank with DU145 cells, and when tumors reached a volume of 200 mm3, the mice were randomized to control (water; daily gavage), 15 mg lycopene/kg BW (daily gavage), 5 or 10 mg docetaxel/kg BW (3 times weekly), or the combination of lycopene and 5 or 10 mg docetaxel/kg BW (79). Lycopene alone had no significant effect on DU145 tumor growth or final tumor weight, and blood lycopene concentrations were not defined in this study to aid comparison with other studies. Docetaxel reduced tumor growth and final tumor weight, and the combination of lycopene and docetaxel was significantly better at inhibiting tumor growth than docetaxel alone after 14 d of treatment. The mechanisms, either directly on the tumor cells or indirect effects of lycopene on the host, to impact efficacy of taxane chemotherapy are unknown and warrant investigation.
Tomato product compared with lycopene and androgen-independent xenografts
The androgen-independent cell line, PC-3, has shown mixed responses to dietary lycopene and tomato paste. Twice-weekly oral lycopene dosing (4 or 16 mg lycopene/kg BW) over 8 wk significantly reduced tumor volume in BALB/c athymic nude mice carrying PC-3 xenografts (Table 4) (80). Excised tumor weights were similarly reduced by 4 mg lycopene/kg BW and 16 mg lycopene/kg BW (80). In contrast, when NMRI nude mice with PC-3 xenografts were fed either control diets or 10% tomato paste–containing diets (providing 2.6 mg lycopene/kg BW) starting 1 wk before graft placement through 5 wk post implantation, there were no differences in end-of-study (5 wk) tumor volume or growth during the study (81). Due to the limited number of studies, conclusions regarding tomato or lycopene impact on the growth of androgen-independent xenografts are uncertain.
Dose–response effect of lycopene on androgen-dependent and -independent xenografts
The dose-dependent effects of a 7-d oral lycopene treatment (0, 1, 5, 10 mg/kg BW) at the beginning of androgen-sensitive (LNCaP) and independent (PC-3 and DU145) xenograft tumorigenesis over 180 d in Balb/c nude mice were compared (82). Remarkably, the 7-d lycopene treatment led to a significant dose-dependent increase in survival and reduction in final tumor volume in all 3 xenograft models. Blood lycopene concentrations in response to the oral doses were not described. Such a result suggests that lycopene dosing impacted early processes related to survival of implanted cells and initial steps in establishing a hospitable environment for xenograft growth.
Summary of studies of tomato and lycopene on prostate tumorigenesis
In summary, the tumorigenesis studies are limited in number and vary in dose provided with mixed support for the impact of lycopene on the growth of rodent and human androgen-dependent and independent cancers. Ideally, a comprehensive study of a dose range of tomato components or lycopene, with similar methodology should be undertaken, complemented by correlations with blood and tissue concentrations of bioactive compounds including lycopene. However, the results do generally indicate a dose-dependent anticancer effect of lycopene in the range that corresponds with the lower range of blood lycopene concentrations observed in humans (53). Unfortunately, many studies do not report blood or tissue concentrations of lycopene, which thus severely compromises our ability to interpret the findings. Although many studies do report the dose of lycopene or dietary intervention provided to rodents, scaling the dose to interpret its relevance to human dietary intake is challenging, due to different rates of absorption and metabolisms and therapeutic windows of lycopene exposures. When considering the results of these studies, one must remain aware of the many different characteristics across the cell lines, and the potential for other factors to impact results and mechanisms of action such as orthotopic compared with subcutaneous implantation, timing of intervention, dose of dietary component, and genetics of the host.
Potential Mechanisms of Action Explored in Rodent Studies
The precise mechanisms whereby lycopene or the diverse array of bioactive compounds in tomato products might impact prostate carcinogenesis are unclear and several reviews of the literature are available (38, 72, 73, 83–86). In brief, most of the research on mechanisms focuses upon a direct impact of lycopene on prostate epithelial cells or cancer cells as opposed to an indirect effect on host processes to impact the carcinogenesis cascade. However, we must also consider the contributions of other carotenoids in tomatoes including phytoene and phytofluene, biosynthetic carotenoid precursors to lycopene abundant in tomatoes, and various other noncarotenoid bioactive compounds that could combine to produce anticancer effects through complementary and additive pathways and mechanisms impacting both the host and developing cancer (4, 87–89).
Evaluation of mechanisms whereby new drugs or chemopreventive agents might act often employs in vitro studies of specific cell lines. Unfortunately, lycopene provides some challenges for cell culture studies because, as a hydrophobic antioxidant, it is both challenging to solubilize and to protect from rapid oxidation without the addition of other potent antioxidant additives. Lycopene can be delivered to cell cultures dissolved in strong solvent, detergents, lipid micelles, or in serum (e.g., references 90–93). Regardless of the carrier, careful consideration should be paid to the effects of the carrier on the accessibility of lycopene in the experiment and on the potential generation of oxidative metabolites, which might also exert bioactivities (e.g., references 94–97).
The most widely considered hypothesis regarding lycopene bioactivity focuses upon its potential as an antioxidant; indeed, due to its structure lycopene is the most potent quencher of singlet oxygen among carotenoids (98, 99). Perhaps lycopene can protect vulnerable cells from oxidative stress, potentially limiting oxidative damage to DNA and other macromolecules that in some way promotes carcinogenesis (98, 100–102). However, the in vivo antioxidant roles of lycopene or other putative antioxidants remain difficult to measure and prove (73). Oxidative stress can also promote inflammation, and data suggest that carotenoids disrupt this cycle to reduce inflammation (reviewed in 85). Indeed, one study indicated that lycopene treatment reduced tumoral expression of NF-κB, a family of inflammation-related transcription factors, as well as proinflammatory cytokine expression (82). Future efforts exploring how lycopene might interface with other antioxidant nutrients and phytochemicals within the complex cellular antioxidant defense system, as well as the parallel cellular repair processes, are warranted.
Evaluation of gene expression patterns in vitro or in vivo suggest that lycopene can inhibit cancer cell growth or carcinogenesis by impacting, either directly or indirectly, processes related to cellular proliferation, survival, androgen sensitivity, and apoptosis (94, 103–105). The studies in rodents suggest the potential for indirect processes related to endocrine, autocrine, and paracrine signaling networks to impact prostate cell biology. Testosterone is absolutely required for normal prostate growth and is implicated as a critical promoter in prostate cancer development (106). How lycopene and other tomato components, either alone or in combination, influence androgen signaling pathways will be key to understanding its role in prostate carcinogenesis (39). Clearly, our recent studies in the TRAMP model suggest that castrate-resistant prostate cancer is no longer sensitive to the inhibitory action of tomato or lycopene (56). IGF-1 is another hormone implicated in human prostate carcinogenesis (107), and laboratory studies demonstrated the ability of tomato components to impact the IGF-1 signaling network (60, 108, 109). We and others have reported that tomato polyphenols inhibit tumor-promoting IGF-1 signaling cascades in prostate cancer cells (109–113). These are but 2 examples of the dozens of regulatory hormones (e.g., steroid family, bioactive lipids, and proteins) that impact the prostate and likely impact carcinogenesis.
In recent years, significant insight has emerged regarding how epithelial cancer development is impacted by the dynamic and complex interactions within the tissue microenvironment (86). For example, many men experience episodic or chronic infections and activation of inflammatory cascades (e.g., prostatitis) that are hypothesized to contribute to prostate cancer development (114, 115). Very little is known regarding how dietary components might impact these processes to alter carcinogenesis in the prostate. Another key step in cancer progression is related to the development of a vascular system to support a growing malignant focus, a process termed angiogenesis (116, 117). Indeed, the growth of cancer beyond a millimeter in size requires new vasculature to provide oxygen, nutrients, and structural substrates, and removal of metabolic waste (116). Biomarkers of enhanced angiogenesis are strongly associated with aggressive prostate cancer. Evaluation of prostate cancer samples in epidemiological studies shows that greater dietary lycopene intake is associated with a lower risk of lethal prostate cancer and reduced angiogenesis biomarkers (118). How tomato components modulate angiogenesis is open to speculation (105).
Cleavage products of lycopene have been hypothesized to convey biological activity (119). Some lycopene metabolites have been detected in tomato products as well as in serum and tissues of rodents and in human serum (120–122). There are 2 primary carotenoid-metabolizing enzymes in mammals, β-carotene 15,15′-oxygenase (BCO1, responsible for central cleavage of carotenoids) and β-carotene 9′,10′-oxygenase (BCO2, responsible for eccentric cleavage of carotenoids), both of which appear to exhibit lycopene cleavage activity (70, 71, 123). We found that ablation of Bco2 in mice reduced the efficacy of a lycopene-containing diet to inhibit TRAMP carcinogenesis, supporting the hypothesis of Bco2-generated lycopene metabolite bioactivity. Most investigations of lycopene metabolite bioactivity have been conducted with supra- or pharmacological concentrations in cell culture (94–96, 124) and models of liver disease and cancer (125–127). Recent evidence suggests that the lycopene metabolite, apo-10′-lycopenoic acid, can inhibit angiogenesis and cell migration (128). The lycopene metabolite, apo-12′-lycopenal, might act by inhibiting prostate cancer cell proliferation, as demonstrated in vitro (94). The lycopene metabolites apo-13-lycopenone and apo-15-lycopenal behave as retinoic acid receptor antagonists (97); however, these metabolites were not detectable in human plasma after a 4-wk high-lycopene dietary intervention (122). Studies to assess metabolite formation in target tissues such as the prostate have not been accomplished. At this time we have intriguing, but very limited mechanistic data regarding the processes by which lycopene metabolites might impact prostate cancer risk.
Discussion
Do tomatoes or lycopene have anti–prostate cancer activity in rodent models? The published literature is largely affirmative, for both tomato products and lycopene. Such findings are supportive of the hypothesis evolving from epidemiological studies (1, 59). Of course we are concerned regarding the potential of reporting bias. Currently, experimental rodent studies reported are heterogeneous in design, lycopene or tomato component doses, reporting of biomarkers of internal exposure (blood and tissue concentrations of bioactive compounds), and examination of a variety of histopathological outcomes. Thus, meta-analyses and pooling projects, as typically done in the epidemiological and clinical literature, are not scientifically justified. Importantly, future studies should precisely report the lycopene dose provided, provide detailed analytic data on tomato components provided, assess internal lycopene (or other dietary component or metabolite) exposure in terms of plasma/serum and tissue concentrations, and carefully consider endpoints along the carcinogenesis cascade that can be related to human disease. The variation in impact by tomato products, intact lycopene, lycopene metabolites, or other tomato phytochemicals in various rodent models should be viewed as an opportunity to better understand relevant mechanisms of action. We are gaining greater appreciation that human prostate cancer, both from genomic analysis and clinical observation, is a very heterogeneous collection of disease subtypes. It is useful to conceptualize specific rodent models as potentially representing subtypes of human cancer and its evolution over time (30, 129). For example, findings can suggest that lycopene mitigates the cascade of genetic damage resulting from loss of TRP53 and RB functioning, both affected in TRAMP and Lady models (36, 57, 58). However, our recent findings suggest that tomato or lycopene has minimal impact on the emergence of castration-resistant cancer in the TRAMP model (56). The limited number of studies prevent any firm conclusions regarding a stronger impact on early carcinogenesis or a weaker impact on tumorigenesis, but bring to light the hypothesis that lycopene might have a greater impact when introduced early in carcinogenesis compared with pharmacological adjuvant therapy of advanced prostate cancer.
In general, lycopene has emerged as a key component of tomato products that can impact carcinogenesis in rodent models. In some models lycopene provided anticancer activity similar to that of whole tomato components, but not in all systems. Most informative are studies that have compared both lycopene and whole tomato in the same experiment (33–36). Konijeti et al. (35) observed that lycopene feeding significantly reduced the tumor incidence in TRAMP mice, from 95% in control to 60% (P < 0.002) whereas lycopene-matched tomato paste did not decrease tumor incidence. Alternatively, Tan et al. (36) found that tomato and lycopene feeding were similarly effective in reducing cancer incidence in TRAMP mice. However, Boileau et al. (33) found that feeding tomato powder increased survival in the NMU-carcinogenesis rat model at 50 wk, whereas lycopene did not. Canene-Adams et al. (34) observed that 10% tomato powder diet slowed tumor growth to a greater degree than lycopene alone in the Dunning implantable tumor rat model. Each study provided different doses of lycopene and the studies modeled different disease outcomes (cancer incidence, survival, and/or tumor size), so it is not surprising that one cannot draw a global conclusion for the relative efficacy of lycopene compared with tomato feeding for all prostate cancer outcomes.
The timing and duration of the tomato or lycopene dietary intervention during prostate carcinogenesis are associated with outcomes in several of the preclinical model studies, with early feeding initiation typically being more effective than later introduction (48, 57, 74, 81). Furthermore, the early introduction does lead to observable changes in gene expression and histology prior to the development of adenocarcinoma (39, 55). These findings warrant further study of tomato and lycopene in men at risk of prostate cancer or in very early stages of prostate carcinogenesis.
That lycopene and tomato tend to be more effective in de novo carcinogenesis and with earlier introduction to the diet is consistent with the recent epidemiological findings suggesting that long-term lycopene intake in men was more predictive of cancer risk than lycopene intakes reported closer to the time of diagnosis (118). A similar finding has recently emerged associating tomato intake in adolescence and reduced later prostate cancer risk (130), as well as early carotenoid intake in adolescent women with a reduced risk of benign breast disease, a risk factor for breast cancer (131, 132). In contrast to the de novo carcinogenesis systems, we found 9 publications with transplantable tumorigenesis systems, with 7 demonstrating a significant inhibition of tumorigenesis when mice were fed a diet containing tomato or lycopene. Three of these 7 studies demonstrate a statistically significant impact of lycopene only when combined with other agents (34, 77, 79) (Table 4). Further along the cancer cascade, lycopene in combination with a therapeutic agent led to slower tumor growth than therapeutic agent alone (79), and was recently found to reduce damage of noncancer tissue from radiation therapy (133), suggesting a role for lycopene as an adjuvant to some standard therapies.
Combining dietary components that have unique mechanisms of action but additive or synergistic impact on cancer is a principle that is supported by successes in cancer chemotherapy with combinations of agents with nonoverlapping toxicity. In some cases, these combinations have proven to be more effective than the single agents, as in the case of whole tomato powder being combined with broccoli powder (34), soy germ (66), or FruHis (40). Similarly, when lycopene was combined with docetaxel (79) or vitamin E (77), these compounds were more effective than either alone. However, in other models there was no benefit when lycopene was combined with vitamin E and/or selenium (76) or vitamin E (61). These observations have stimulated food scientists to develop novel food products combining these components for future human studies (19, 21).
Overall, the tomato, lycopene, and prostate cancer prevention hypothesis is largely supported by experimental animal studies, suggesting a need for additional mechanistic testing in modern genetically engineered mouse models. With an ever-improving understanding of molecular genetics and associated biological implications in human prostate cancer, new genetically engineered mouse models are being developed. These models along with genomic, transcriptomic, and proteomic tools should be leveraged to pinpoint the pathways through which lycopene and tomato components disrupt carcinogenesis. Such studies will help to inform variable selection for future epidemiological studies and tumor-based inclusion criteria for clinical trials of tomato or lycopene products.
ACKNOWLEDGEMENTS
We thank Nikki A Ford, PhD for her contributions to the initial manuscript draft. The authors’ responsibilities were as follows—NEM, SKC: wrote and revised the manuscript; JMT-A, LW, KEZ, JWE: provided critical editing; and all authors: read and approved the final manuscript.
Notes
Support was provided by the National Cancer Institute under award number R01 CA125384 (JWE and SKC), the USDA Agricultural Research Service under CRIS 3092-51000-056-03S and 3092-51000-059-NEW2S (NEM), and a Pelotonia Postdoctoral Fellowship (NEM). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of Pelotonia, the USDA/ARS, or NIH NCI.
Author disclosures: The authors report no conflicts of interest. JWE is a member of the Journal's Editorial Board.
Abbreviations used: BCO, β-carotene oxygenase; BW, body weight; DMAB, 3,2′-dimethyl-4-amino-biphenyl; FruHis, fructose-histidine; GEM, genetically engineered mouse; HPFS, Health Professionals Follow-up Study; IGF-1, insulin-like growth factor 1; NMU, N-methyl-N-nitrosourea; PhIP, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine; PIN, prostatic intraepithelial neoplasia; PSA, prostate-specific antigen; RB1, retinoblastoma transcriptional corepressor 1; SV40, simian virus 40; Tag, large T antigen; TRAMP, transgenic adenocarcinoma of the mouse prostate; TRP53, transformation related protein 53.
Contributor Information
Nancy E Moran, USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Jennifer M Thomas-Ahner, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Lei Wan, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Interdisciplinary Nutrition Program, The Ohio State University, Columbus, OH, USA.
Krystle E Zuniga, Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Livestrong Cancer Institutes, Dell Medical School, University of Texas, Austin, TX, USA.
John W Erdman, Jr, Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA.
Steven K Clinton, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
References
- 1. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst. 1995;87(23):1767–76. [DOI] [PubMed] [Google Scholar]
- 2. Giovannucci E. Does prostate-specific antigen screening influence the results of studies of tomatoes, lycopene, and prostate cancer risk?. J Natl Cancer Inst. 2007;99(14):1060–2. [DOI] [PubMed] [Google Scholar]
- 3. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002;94(5):391–8. [DOI] [PubMed] [Google Scholar]
- 4. Tan HL, Thomas-Ahner JM, Grainger EM, Wan L, Francis DM, Schwartz SJet al. Tomato-based food products for prostate cancer prevention: what have we learned?. Cancer Metastasis Rev. 2010;29(3):553–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Clinton SK. Tomatoes or lycopene: a role in prostate carcinogenesis?. J Nutr. 2005;135(8):2057S–9S. [DOI] [PubMed] [Google Scholar]
- 6. Kristal AR. Vitamin A, retinoids and carotenoids as chemopreventive agents for prostate cancer. J Urol. 2004;171(2S):S54–8.; discussion S8. [DOI] [PubMed] [Google Scholar]
- 7. Kristal AR, Cohen JH. Invited commentary: tomatoes, lycopene, and prostate cancer. How strong is the evidence? Am J Epidemiol. 2000;151(2):124–7.; discussion 128–30. [DOI] [PubMed] [Google Scholar]
- 8. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91(4):317–31. [DOI] [PubMed] [Google Scholar]
- 9. Wei MY, Giovannucci EL. Lycopene, tomato products, and prostate cancer incidence: a review and reassessment in the PSA screening era. J Oncol. 2012;2012:271063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. World Cancer Research Fund . Food, nutrition and the prevention of cancer: a global perspective. Washington (DC): American Institute for Cancer Research; 2007. [Google Scholar]
- 11. World Cancer Research Fund, American Institute for Cancer Research . Continuous update project expert report. Diet, nutrition, physical activity and prostate cancer, 2018. [Internet] [cited: 4 Feb 2019]. Available from: dietandcancerreport.org. [Google Scholar]
- 12. Mucci LA, Powolny A, Giovannucci E, Liao Z, Kenfield SA, Shen Ret al. Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study. J Clin Oncol. 2009;27(33):5627–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Agricultural Research Service . Nutrient intakes from food and beverages: mean amounts consumed per individual, by gender and age, in the United States, 2015–2016. Beltsville (MD): US Department of Agriculture, 2018i. [Google Scholar]
- 14. Miller EC, Hadley CW, Schwartz SJ, Erdman JW Jr, Boileau TW-M, Clinton SK. Lycopene, tomato products, and prostate cancer prevention. Have we established causality?. Pure Appl Chem. 2002;74(8):1435–41. [Google Scholar]
- 15. van Breemen RB, Sharifi R, Viana M, Pajkovic N, Zhu D, Yuan Let al. Antioxidant effects of lycopene in African American men with prostate cancer or benign prostate hyperplasia: a randomized, controlled trial. Cancer Prev Res. 2011;4(5):711–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Gustin DM, Rodvold KA, Sosman JA, Diwadkar-Navsariwala V, Stacewicz-Sapuntzakis M, Viana Met al. Single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male subjects. Cancer Epidemiol Biomarkers Prev. 2004;13:850–60. [PubMed] [Google Scholar]
- 17. Kim HS, Bowen P, Chen L, Duncan C, Ghosh L, Sharifi Ret al. Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer. 2003;47(1):40–7. [DOI] [PubMed] [Google Scholar]
- 18. Diwadkar-Navsariwala V, Novotny JA, Gustin DM, Sosman JA, Rodvold KA, Crowell JAet al. A physiological pharmacokinetic model describing the disposition of lycopene in healthy men. J Lipid Res. 2003;44(10):1927–39. [DOI] [PubMed] [Google Scholar]
- 19. Bohn T, Blackwood M, Francis D, Tian Q, Schwartz SJ, Clinton SK. Bioavailability of phytochemical constituents from a novel soy fortified lycopene rich tomato juice developed for targeted cancer prevention trials. Nutr Cancer. 2013;65:919–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Grainger EM, Schwartz SJ, Wang S, Unlu NZ, Boileau TW, Ferketich AKet al. A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen. Nutr Cancer. 2008;60(2):145–54. [DOI] [PubMed] [Google Scholar]
- 21. Grainger EM, Moran NE, Francis DM, Schwartz SJ, Wan L, Thomas-Ahner Jet al. A novel tomato-soy juice induces a dose-response increase in urinary and plasma phytochemical biomarkers in men with prostate cancer. J Nutr. 2019;149(1):26–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Moran NE, Thomas-Ahner J, Fleming JL, McElroy JP, Mehl R, Grainger EM, Riedl KMet al. SNPs in beta-carotene oxygenase 1 are associated with plasma lycopene responses to a tomato-soy juice intervention in men with prostate cancer. J Nutr. 2019;149(3):381–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Unlu NZ, Bohn T, Clinton SK, Schwartz SJ. Carotenoid absorption from salad and salsa by humans is enhanced by the addition of avocado or avocado oil. J Nutr. 2005;135(3):431–6. [DOI] [PubMed] [Google Scholar]
- 24. Unlu NZ, Bohn T, Francis DM, Nagaraja HN, Clinton SK, Schwartz SJ. Lycopene from heat-induced cis-isomer-rich tomato sauce is more bioavailable than from all-trans-rich tomato sauce in human subjects. Br J Nutr. 2007;98(1):140–6. [DOI] [PubMed] [Google Scholar]
- 25. Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997;66(1):116–22. [DOI] [PubMed] [Google Scholar]
- 26. Ittmann M, Huang J, Radaelli E, Martin P, Signoretti S, Sullivan Ret al. Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res. 2013;73(9):2718–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Grabowska MM, DeGraff DJ, Yu X, Jin RJ, Chen Z, Borowsky ADet al. Mouse models of prostate cancer: picking the best model for the question. Cancer Metastasis Rev. 2014;33(2-3):377–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Navone NM, Logothetis CJ, von Eschenbach AC, Troncoso P. Model systems of prostate cancer: uses and limitations. Cancer Metastasis Rev. 1998;17(4):361–71. [DOI] [PubMed] [Google Scholar]
- 29. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos Eet al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AYet al. The genomic complexity of primary human prostate cancer. Nature. 2011;470(7333):214–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Institute of Medicine (US) Panel on Micronutrients . Beta-carotene and other carotenoids. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington (DC): National Academies Press (US); 2000. [PubMed] [Google Scholar]
- 32. Jilcott Pitts SB, Moran NE, Wu Q, Harnack L, Craft NE, Hanchard Net al. Pressure-mediated reflection spectroscopy criterion validity as a biomarker of fruit and vegetable intake: a 2-site cross-sectional study of 4 racial or ethnic groups. J Nutr. 2022;152:107–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK. Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst. 2003;95(21):1578–86. [DOI] [PubMed] [Google Scholar]
- 34. Canene-Adams K, Lindshield BL, Wang S, Jeffery EH, Clinton SK, Erdman JW Jr. Combinations of tomato and broccoli enhance antitumor activity in Dunning r3327-h prostate adenocarcinomas. Cancer Res. 2007;67(2):836–43. [DOI] [PubMed] [Google Scholar]
- 35. Konijeti R, Henning S, Moro A, Sheikh A, Elashoff D, Shapiro Aet al. Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate. 2010;70(14):1547–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Tan HL, Thomas-Ahner JM, Moran NE, Cooperstone JL, Erdman JW Jr, Young GSet al. beta-Carotene 9′,10′ oxygenase modulates the anticancer activity of dietary tomato or lycopene on prostate carcinogenesis in the TRAMP model. Cancer Prev Res. 2017;10(2):161–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev. 1998;56(2):35–51. [DOI] [PubMed] [Google Scholar]
- 38. Heber D, Lu QY. Overview of mechanisms of action of lycopene. Exp Biol Med. 2002;227(10):920–3. [DOI] [PubMed] [Google Scholar]
- 39. Wan L, Tan HL, Thomas-Ahner JM, Pearl DK, Erdman JW Jr, Moran NEet al. Dietary tomato and lycopene impact androgen signaling- and carcinogenesis-related gene expression during early TRAMP prostate carcinogenesis. Cancer Prev Res. 2014;7(12):1228–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Mossine VV, Chopra P, Mawhinney TP. Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res. 2008;68(11):4384–91. [DOI] [PubMed] [Google Scholar]
- 41. Irshad S, Abate-Shen C. Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic. Cancer Metastasis Rev. 2013;32(1-2):109–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Klein RD. The use of genetically engineered mouse models of prostate cancer for nutrition and cancer chemoprevention research. Mutat Res. 2005;576(1-2):111–19. [DOI] [PubMed] [Google Scholar]
- 43. Sharma P, Schreiber-Agus N. Mouse models of prostate cancer. Oncogene. 1999;18(38):5349–55. [DOI] [PubMed] [Google Scholar]
- 44. Hensley PJ, Kyprianou N. Modeling prostate cancer in mice: limitations and opportunities. J Androl. 2012;33(2):133–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Waters DJ, Bostwick DG, Murphy GP. Conference summary: First International Workshop on Animal Models of Prostate Cancer. Prostate. 1998;36(1):47–8. [DOI] [PubMed] [Google Scholar]
- 46. Pienta KJ, Abate-Shen C, Agus DB, Attar RM, Chung LW, Greenberg NMet al. The current state of preclinical prostate cancer animal models. Prostate. 2008;68(6):629–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, Group N. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160(7):1577–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Imaida K, Tamano S, Kato K, Ikeda Y, Asamoto M, Takahashi Set al. Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis. Carcinogenesis. 2001;22(3):467–72. [DOI] [PubMed] [Google Scholar]
- 49. Shirai T, Takahashi S, Cui L, Futakuchi M, Kato K, Tamano Set al. Experimental prostate carcinogenesis – rodent models. Mut Res Rev Mutat Res. 2000;462(2-3):219–26. [DOI] [PubMed] [Google Scholar]
- 50. Nascimento-Goncalves E, Faustino-Rocha AI, Seixas F, Ginja M, Colaco B, Ferreira Ret al. Modelling human prostate cancer: rat models. Life Sci. 2018;203:210–24. [DOI] [PubMed] [Google Scholar]
- 51. Bosland MC. Animal models for the study of prostate carcinogenesis. J Cell Biochem. 1992;50(S16H):89–98. [DOI] [PubMed] [Google Scholar]
- 52. Grainger EM, Hadley CW, Moran NE, Riedl KM, Gong MC, Pohar Ket al. A comparison of plasma and prostate lycopene in response to typical servings of tomato soup, sauce or juice in men before prostatectomy. Br J Nutr. 2015;114(4):596–607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Shardell MD, Alley DE, Hicks GE, El-Kamary SS, Miller RR, Semba RDet al. Low-serum carotenoid concentrations and carotenoid interactions predict mortality in US adults: the Third National Health and Nutrition Examination Survey. Nutr Res. 2011;31(3):178–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Canene-Adams K, Sfanos KS, Liang CT, Yegnasubramanian S, Nelson WG, Brayton Cet al. Dietary chemoprevention of PhIP induced carcinogenesis in male Fischer 344 rats with tomato and broccoli. PLoS One. 2013;8(11):e79842. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Pannellini T, Iezzi M, Liberatore M, Sabatini F, Iacobelli S, Rossi Cet al. A dietary tomato supplement prevents prostate cancer in TRAMP mice. Cancer Prev Res. 2010;3(10):1284–91. [DOI] [PubMed] [Google Scholar]
- 56. Rowles JL, Smith JW, Applegate CC, Miller RJ, Wallig MA, Kaur Aet al. Dietary tomato or lycopene do not reduce castration-resistant prostate cancer progression in a murine model. J Nutr. 2020;150(7):1808–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH. Antioxidants block prostate cancer in lady transgenic mice. Cancer Res. 2004;64(16):5891–6. [DOI] [PubMed] [Google Scholar]
- 58. Venkateswaran V, Klotz LH, Ramani M, Sugar LM, Jacob LE, Nam RKet al. A combination of micronutrients is beneficial in reducing the incidence of prostate cancer and increasing survival in the Lady transgenic model. Cancer Prev Res. 2009;2(5):473–83. [DOI] [PubMed] [Google Scholar]
- 59. Key TJ, Appleby PN, Travis RC, Albanes D, Alberg AJ, Barricarte Aet al. Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies. Am J Clin Nutr. 2015;102(5):1142–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60. Herzog A, Siler U, Spitzer V, Seifert N, Denelavas A, Hunziker PBet al. Lycopene reduced gene expression of steroid targets and inflammatory markers in normal rat prostate. FASEB J. 2005;19(2):1–24. [DOI] [PubMed] [Google Scholar]
- 61. Siler U, Barella L, Spitzer V, Schnorr J, Lein M, Goralczyk Ret al. Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. FASEB J. 2004;18(9):1019–21. [DOI] [PubMed] [Google Scholar]
- 62. Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. Am J Clin Nutr. 2009;89(4):1155–63. [DOI] [PubMed] [Google Scholar]
- 63. Mahmoud AM, Yang W, Bosland MC. Soy isoflavones and prostate cancer: a review of molecular mechanisms. J Steroid Biochem Mol Biol. 2014;140:116–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, Clinton SK. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr. 1999;129(9):1628–35. [DOI] [PubMed] [Google Scholar]
- 65. Aronson WJ, Tymchuk CN, Elashoff RM, McBride WH, McLean C, Wang Het al. Decreased growth of human prostate LNCaP tumors in SCID mice fed a low-fat, soy protein diet with isoflavones. Nutr Cancer. 1999;35(2):130–6. [DOI] [PubMed] [Google Scholar]
- 66. Zuniga K, Clinton SK, Erdman JW Jr. The interactions of dietary tomato powder and soy germ on prostate carcinogenesis in the TRAMP model. Cancer Prev Res. 2013;6(6):548–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Bohn T, Desmarchelier C, Dragsted LO, Nielsen CS, Stahl W, Ruhl Ret al. Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans. Mol Nutr Food Res. 2017;61:1600685. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Moran NE, Mohn ES, Hason N, Erdman JW Jr, Johnson EJ. Intrinsic and extrinsic factors impacting absorption, metabolism, and health effects of dietary carotenoids. Adv Nutr. 2018;9(4):465–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Lobo GP, Amengual J, Palczewski G, Babino D, von Lintig J. Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids. 2012;1821(1):78–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70. dela Sena C, Narayanasamy S, Riedl KM, Curley RW Jr, Schwartz SJ, Harrison EH. Substrate specificity of purified recombinant human beta-carotene 15,15′-oxygenase (BCO1). J Biol Chem. 2013;288(52):37094–103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71. Dela Sena C, Sun J, Narayanasamy S, Riedl KM, Yuan Y, Curley RW Jret al. Substrate specificity of purified recombinant chicken beta-carotene 9',10'-oxygenase (BCO2). J Biol Chem. 2016;291(28):14609–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. Ford NA, Erdman JW Jr. Are lycopene metabolites metabolically active?. Acta Biochim Pol. 2012;59(1):1–4. [PubMed] [Google Scholar]
- 73. Erdman JW Jr, Ford NA, Lindshield BL. Are the health attributes of lycopene related to its antioxidant function?. Arch Biochem Biophys. 2009;483(2):229–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74. Conlon LE, Wallig MA, Erdman JW Jr. Low-lycopene containing tomato powder diet does not protect against prostate cancer in TRAMP mice. Nutr Res. 2015;35(10):882–90. [DOI] [PubMed] [Google Scholar]
- 75. Tennant TR, Kim H, Sokoloff M, Rinker-Schaeffer CW. The Dunning model. Prostate. 2000;43(4):295–302. [DOI] [PubMed] [Google Scholar]
- 76. Lindshield BL, Ford NA, Canene-Adams K, Diamond AM, Wallig MA, Erdman JW Jr. Selenium, but not lycopene or vitamin E, decreases growth of transplantable dunning R3327-H rat prostate tumors. PLoS One. 2010;5(4):e10423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77. Limpens J, Schroder FH, de Ridder CM, Bolder CA, Wildhagen MF, Obermuller-Jevic UCet al. Combined lycopene and vitamin E treatment suppresses the growth of PC-346C human prostate cancer cells in nude mice. J Nutr. 2006;136(5):1287–93. [DOI] [PubMed] [Google Scholar]
- 78. Tang L, Jin T, Zeng X, Wang JS. Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr. 2005;135(2):287–90. [DOI] [PubMed] [Google Scholar]
- 79. Tang Y, Parmakhtiar B, Simoneau AR, Xie J, Fruehauf J, Lilly Met al. Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia. 2011;13(2):108–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80. Yang CM, Yen YT, Huang CS, Hu ML. Growth inhibitory efficacy of lycopene and beta-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol Nutr Food Res. 2011;55(4):606–12. [DOI] [PubMed] [Google Scholar]
- 81. Kolberg M, Pedersen S, Bastani NE, Carlsen H, Blomhoff R, Paur I. Tomato paste alters NF-kappaB and cancer-related mRNA expression in prostate cancer cells, xenografts, and xenograft microenvironment. Nutr Cancer. 2015;67(2):305–15. [DOI] [PubMed] [Google Scholar]
- 82. Jiang LN, Liu YB, Li BH. Lycopene exerts anti-inflammatory effect to inhibit prostate cancer progression. Asian J Androl. 2018;21:80–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83. Mein JR, Lian F, Wang XD. Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev. 2008;66(12):667–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84. Sharoni Y, Linnewiel-Hermoni K, Zango G, Khanin M, Salman H, Veprik Aet al. The role of lycopene and its derivatives in the regulation of transcription systems: implications for cancer prevention. Am J Clin Nutr. 2012;96(5):1173S–8S. [DOI] [PubMed] [Google Scholar]
- 85. Kaulmann A, Bohn T. Carotenoids, inflammation, and oxidative stress—implications of cellular signaling pathways and relation to chronic disease prevention. Nutr Res. 2014;34(11):907–29. [DOI] [PubMed] [Google Scholar]
- 86. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. [DOI] [PubMed] [Google Scholar]
- 87. Engelmann NJ, Clinton SK, Erdman JW Jr. Nutritional aspects of phytoene and phytofluene, carotenoid precursors to lycopene. Adv Nutr. 2011;2(1):51–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88. Canene-Adams K, Campbell JK, Zaripheh S, Jeffery EH, Erdman JW Jr. The tomato as a functional food. J Nutr. 2005;135(5):1226–30. [DOI] [PubMed] [Google Scholar]
- 89. Campbell JK, Canene-Adams K, Lindshield BL, Boileau TW, Clinton SK, Erdman JW Jr. Tomato phytochemicals and prostate cancer risk. J Nutr. 2004;134(12):3486S–92S. [DOI] [PubMed] [Google Scholar]
- 90. Lin CY, Huang CS, Hu ML. The use of fetal bovine serum as delivery vehicle to improve the uptake and stability of lycopene in cell culture studies. Br J Nutr. 2007;98(1):226–32. [DOI] [PubMed] [Google Scholar]
- 91. Williams AW, Boileau TW, Clinton SK, Erdman JW Jr. beta-Carotene stability and uptake by prostate cancer cells are dependent on delivery vehicle. Nutr Cancer. 2000;36(2):185–90. [DOI] [PubMed] [Google Scholar]
- 92. O'Sullivan SM, Woods JA, O'Brien NM. Use of Tween 40 and Tween 80 to deliver a mixture of phytochemicals to human colonic adenocarcinoma cell (CaCo-2) monolayers. Br J Nutr. 2004;91(5):757–64. [DOI] [PubMed] [Google Scholar]
- 93. Sy C, Gleize B, Dangles O, Landrier JF, Veyrat CC, Borel P. Effects of physicochemical properties of carotenoids on their bioaccessibility, intestinal cell uptake, and blood and tissue concentrations. Mol Nutr Food Res. 2012;56(9):1385–97. [DOI] [PubMed] [Google Scholar]
- 94. Ford NA, Elsen AC, Zuniga K, Lindshield BL, Erdman JW Jr. Lycopene and apo-12′-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer. 2011;63(2):256–63. [DOI] [PubMed] [Google Scholar]
- 95. Yang CM, Hu TY, Hu ML. Antimetastatic effects and mechanisms of apo-8'-lycopenal, an enzymatic metabolite of lycopene, against human hepatocarcinoma SK-Hep-1 cells. Nutr Cancer. 2012;64(2):274–85. [DOI] [PubMed] [Google Scholar]
- 96. Yang CM, Huang SM, Liu CL, Hu ML. Apo-8′-lycopenal induces expression of HO-1 and NQO-1 via the ERK/p38-Nrf2-ARE pathway in human Hepg2 cells. J Agric Food Chem. 2012;60(6):1576–85. [DOI] [PubMed] [Google Scholar]
- 97. Narayanasamy S, Sun J, Pavlovicz RE, Eroglu A, Rush CE, Sunkel BDet al. Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists. J Lipid Res. 2017;58(5):1021–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98. Rao A, Agarwal S. Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr Res. 1999;19:305–23. [Google Scholar]
- 99. Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys. 1989;274(2):532–8. [DOI] [PubMed] [Google Scholar]
- 100. Rao AV, Agarwal S. Role of antioxidant lycopene in cancer and heart disease. J Am Coll Nutr. 2000;19(5):563–9. [DOI] [PubMed] [Google Scholar]
- 101. Rao AV, Fleshner N, Agarwal S. Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study. Nutr Cancer. 1999;33(2):159–64. [DOI] [PubMed] [Google Scholar]
- 102. Rao AV, Rao LG. Carotenoids and human health. Pharmacol Res. 2007;55(3):207–16. [DOI] [PubMed] [Google Scholar]
- 103. Hwang ES, Bowen PE. Effects of tomato paste extracts on cell proliferation, cell-cycle arrest and apoptosis in LNCaP human prostate cancer cells. Biofactors. 2005;23(2):75–84. [DOI] [PubMed] [Google Scholar]
- 104. Ivanov NI, Cowell SP, Brown P, Rennie PS, Guns ES, Cox ME. Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr. 2007;26(2):252–63. [DOI] [PubMed] [Google Scholar]
- 105. Cervi D, Pak B, Venier NA, Sugar LM, Nam RK, Fleshner NEet al. Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, platelet factor-4. BMC Cancer. 2010;10(1):258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106. So AI, Hurtado-Coll A, Gleave ME. Androgens and prostate cancer. World J Urol. 2003;21(5):325–37. [DOI] [PubMed] [Google Scholar]
- 107. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson Pet al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study [see comments]. Science. 1998;279(5350):563–6. [DOI] [PubMed] [Google Scholar]
- 108. Wang S, DeGroff VL, Clinton SK. Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. J Nutr. 2003;133(7):2367–76. [DOI] [PubMed] [Google Scholar]
- 109. Kaplan PJ, Mohan S, Cohen P, Foster BA, Greenberg NM. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res. 1999;59:2203–9. [PubMed] [Google Scholar]
- 110. Karas M, Amir H, Fishman D, Danilenko M, Segal S, Nahum Aet al. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer. 2000;36(1):101–11. [DOI] [PubMed] [Google Scholar]
- 111. Nahum A, Zeller L, Danilenko M, Prall OW, Watts CK, Sutherland RLet al. Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1. Eur J Nutr. 2006;45(5):275–82. [DOI] [PubMed] [Google Scholar]
- 112. Kanagaraj P, Vijayababu MR, Ravisankar B, Anbalagan J, Aruldhas MM, Arunakaran J. Effect of lycopene on insulin-like growth factor-I, IGF binding protein-3 and IGF type-I receptor in prostate cancer cells. J Cancer Res Clin Oncol. 2007;133(6):351–9. [DOI] [PubMed] [Google Scholar]
- 113. Liu X, Allen JD, Arnold JT, Blackman MR. Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells. Carcinogenesis. 2008;29(4):816–23. [DOI] [PubMed] [Google Scholar]
- 114. Giri D, Ozen M, Ittmann M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol. 2001;159(6):2159–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115. Sfanos KS, Isaacs WB, De Marzo AM. Infections and inflammation in prostate cancer. Am J Clin Exp Urol. 2013;1:3–11. [PMC free article] [PubMed] [Google Scholar]
- 116. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6Q):15–18. [DOI] [PubMed] [Google Scholar]
- 117. Folkman J. Angiogenesis. Annu Rev Med. 2006;57(1):1–18. [DOI] [PubMed] [Google Scholar]
- 118. Zu K, Mucci L, Rosner BA, Clinton SK, Loda M, Stampfer MJet al. Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. J Natl Cancer Inst 2014;106(2):djt430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119. Kiefer C, Hessel S, Lampert JM, Vogt K, Lederer MO, Breithaupt DEet al. Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A. J Biol Chem. 2001;276(17):14110–16. [DOI] [PubMed] [Google Scholar]
- 120. Gajic M, Zaripheh S, Sun F, Erdman JW Jr. Apo-8′-lycopenal and apo-12′-lycopenal are metabolic products of lycopene in rat liver. J Nutr. 2006;136(6):1552–7. [DOI] [PubMed] [Google Scholar]
- 121. Kopec RE, Riedl KM, Harrison EH, Curley RW Jr, Hruszkewycz DP, Clinton SKet al. Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma. J Agric Food Chem. 2010;58(6):3290–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Cooperstone JL, Novotny JA, Riedl KM, Cichon MJ, Francis DM, Curley RW Jret al. Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: a randomized human clinical trial. Am J Clin Nutr. 2018;108(4):784–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123. Hu KQ, Liu C, Ernst H, Krinsky NI, Russell RM, Wang XD. The biochemical characterization of ferret carotene-9',10'-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. J Biol Chem. 2006;281(28):19327–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124. Takahashi S, Waki N, Mohri S, Takahashi H, Ara T, Aizawa Ket al. Apo-12′-lycopenal, a lycopene metabolite, promotes adipocyte differentiation via peroxisome proliferator-activated receptor gamma activation. J Agric Food Chem. 2018;66(50):13152–61. [DOI] [PubMed] [Google Scholar]
- 125. Chung J, Koo K, Lian F, Hu KQ, Ernst H, Wang XD. Apo-10′-lycopenoic acid, a lycopene metabolite, increases sirtuin 1 mRNA and protein levels and decreases hepatic fat accumulation in ob/ob mice. J Nutr. 2012;142(3):405–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126. Ip BC, Hu KQ, Liu C, Smith DE, Obin MS, Ausman LMet al. Lycopene metabolite, apo-10′-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice. Cancer Prev Res. 2013;6(12):1304–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127. Ip BC, Liu C, Lichtenstein AH, von Lintig J, Wang XD. Lycopene and apo-10′-lycopenoic acid have differential mechanisms of protection against hepatic steatosis in beta-carotene-9′,10′-oxygenase knockout male mice. J Nutr. 2015;145(2):268–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 128. Cheng J, Miao B, Hu KQ, Fu X, Wang XD. Apo-10′-lycopenoic acid inhibits cancer cell migration and angiogenesis and induces peroxisome proliferator-activated receptor gamma. J Nutr Biochem. 2018;56:26–34. [DOI] [PubMed] [Google Scholar]
- 129. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24(18):1967–2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130. Lan T, Park Y, Colditz GA, Liu J, Wang M, Wu Ket al. Adolescent plant product intake in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study. J Nutr. 2021;151(10):3223–31. [DOI] [PubMed] [Google Scholar]
- 131. Boeke CE, Tamimi RM, Berkey CS, Colditz GA, Eliassen AH, Malspeis Set al. Adolescent carotenoid intake and benign breast disease. Pediatrics. 2014;133(5):e1292–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132. Su X, Boeke CE, Collins LC, Baer HJ, Willett WC, Schnitt SJet al. Intakes of fat and micronutrients between ages 13 and 18 years and the incidence of proliferative benign breast disease. Cancer Causes Control. 2015;26(1):79–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133. Rowles JL, Wallig MA, Selting KA, Fan TM, Miller RJ, O'Brien WD, Erdman JW. A 10% tomato diet selectively reduces radiation-induced damage in TRAMP mice. J Nutr. 2021;151(11):3421–30. [DOI] [PubMed] [Google Scholar]