Zu K, Mucci L, Rosner BA, et al. Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. J Natl Cancer Inst. 2014;106(2):djt430.
Ongoing prospective cohort study
This study included 51,529 US male health professionals (dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians) between the ages of 40 and 75 at baseline in 1986.
Study Parameters Assessed
Dietary intake was assessed by self-administered semiquantitative Food Frequency Questionnaire every 4 years from 1986 to 2006; dietary lycopene content was calculated based on US Department of Agriculture data. For some of the men in the study, plasma lycopene levels were also available (n=1,200), for which quintiles of highest to lowest lycopene levels were established. Prostate cancer diagnoses were self-reported on a biennial questionnaire. Medical records were reviewed for data on tumor stage, prostate-specific antigen (PSA) at diagnosis, Gleason score, angiogenic biomarkers, apoptosis, and proliferation. Deaths due to prostate cancer were confirmed by review of medical records, death certificates, and searches of the National Death Index. To assess whether PSA screening affected the association between lycopene intake and prostate cancer incidence, stratified survival analyses were performed for before and after the PSA test was introduced in 1994.
Primary Outcome Measures
Total incidence of prostate cancer in relation to dietary lycopene intake; incidence of lethal or metastasized prostate cancer in relation to dietary intake; and markers of tumor angiogenesis, apoptosis, and proliferation associated with dietary lycopene intake.
In comparison with the lowest quintile of dietary lycopene consumption, the top quintile showed an inverse association between total prostate cancer incidence and early lycopene intake (hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.84–1.00). A stronger inverse association was found between lethal prostate cancers and lycopene intake (HR: 0.72; 95% CI: 0.56–0.94). The strongest inverse association was found in men who had the highest intake at baseline and continued this level of intake (HR: 0.48; 95% CI: 0.30–0.78), as opposed to those who had increased their intake over time. Previous to the introduction of the PSA test in clinical practice, high lycopene intake was found to have a stronger inverse association with total diagnosed prostate cancers, but in the PSA era, only a slight reduction was found in total prostate cancer diagnosis. The lower risk for lethal prostate cancers, however, remained unchanged. There was a strong association between higher lycopene intake and markers of angiogenesis in those subjects who had prostate cancer; these men had tumors with much lower angiogenic potential. Markers of tumor apoptosis and proliferation showed no association with lycopene intake.
This study is the latest of many seeking to elucidate the relationship between lycopene and its potential role in the prevention or treatment of prostate cancer. The large size (N=51,529) and long duration of the study give us a more extensive look at how lifelong habits can influence prostate cancer. The study also gives us an important perspective on how a food constituent, rather than an isolated compound, can alter the course of a disease over time. The data from this study can be used as a tool to help clinicians educate their patients on habits that encourage wellness over a lifetime. In theory, lycopene appears to be an ideal cancer preventative. It is the most potent antioxidant of all the carotenoids, and it activates antioxidant enzymes such as glutathione s-tranferase and superoxide dismutase,1 thus enabling it to prevent cell and DNA damage. There are also many studies that have demonstrated lycopene's ability to disrupt prostate cancer cell growth in culture.1–3 There have been mixed data, however, on how lycopene influences prostate cancer in human subjects.
Men with the highest dietary intake of lycopene also generally consumed more fruits, vegetables, and fiber, all of which been shown to lower the risk of prostate cancer.
While earlier studies showed a more consistent correlation between total prostate cancer diagnoses and high lycopene intake, studies in the past 10 years have had mixed results.4–9 According to the present study, since the advent of PSA testing, there was a more limited difference in the number of diagnosed prostate cancers relative to lycopene intake. However, the research team found a significant difference in the incidence of lethal or metastasized prostate cancers in men with the highest vs the lowest dietary levels of lycopene. It may be that prostate cancer is being diagnosed much earlier since the advent of PSA testing. This also implies that lycopene affects the growth course of prostate cancer rather than preventing the formation of the tumors. Supporting this idea, men with higher lycopene intake and prostate cancer had significantly different markers of angiogenic potential, meaning their tumors were less aggressive.
While there is controversy about the practical value of universal PSA screening due to the overdiagnosis and treatment of indolent cancers,10,11 in this particular study, PSA was a useful surrogate for later biopsy-proven cancers and their association with lycopene intake. The group members who showed the most benefit were consuming the highest amount of lycopene at baseline and continued throughout the years of the study, as opposed to those men who later started higher lycopene food intake. Ideally, incorporating high-lycopene foods into the diet early in life will have the most profound effects on those men who do go on to develop prostate cancer.
As with all whole food studies, there may be other factors at play. For example, there may be other chemicals found in high-lycopene foods that could account for the results or have a synergistic effect with lycopene in the body. This study utilized data calculated from reported intake of lycopene-containing foods rather than supplemented lycopene. Other studies that utilized whole-tomato products have also shown positive results,12,13 while studies using supplemented lycopene have shown less benefit.11,14,15 Additionally, other phytochemicals such as alpha-tomatine, a saponin found in tomato, have been found to inhibit the growth of prostate cancer cells in cell culture and in mice.16,17 Something else to consider is whether there are other factors beyond just the consumption of high lycopene foods that played a role in these findings. For example, in this study, the men with the highest dietary intake of lycopene also generally consumed more fruits, vegetables, and fiber, all of which been shown to lower the risk of prostate cancer.18,19
This study is a good long-term look at how consumption of a certain class of foods can help modify the course of a disease process over time. It is less clinically relevant for patients with prostate cancer in the short term because the effects of lycopene-rich foods on prostate cancer are more pronounced with long-term consumption initiated before the diagnosis of prostate disease. However, the study's results can help guide the clinician in advising his or her patients on their dietary habits. It underlines the necessity for high-quality nutritional counseling as a critical component of the prevention aspect of a routine checkup. This gives the primary clinician one more tool to help improve the long-term health of his or her patients.
- Rafi MM, Kanakasabai S, Reyes MD, Bright JJ. Lycopene modulates growth and survival associated genes in prostate cancer. J Nutr Biochem. 2013;24(10):1724-1734.
- Soares Nda C, Teodoro AJ, Oliveira FL, et al. Influence of lycopene on cell viability, cell cycle, and apoptosis of human prostate cancer and benign hyperplastic cells. Nutr Cancer. 2013;65(7):1076-1085.
- 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):252-263.
- Ilic D, Forbes KM, Hassed C. Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev. 2011;(11 ):CD008007.
- Trejo-Solís C, Pedraza-Chaverrí J, Torres-Ramos M, et al. Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition. Evid Based Complement Alternat Med. 2013;2013:705121.
- Vance TM, Su J, Fontham ET, Koo SI, Chun OK. Dietary antioxidants and prostate cancer: a review. Nutr Cancer. 2013;65(6):793-801.
- Chen J, Song Y, Zhang L. Lycopene/tomato consumption and the risk of prostate cancer: a systematic review and meta-analysis of prospective studies. J Nutr Sci Vitaminol (Tokyo). 2013;59(3):213-223.
- Van Blarigan EL, Ma J, Kenfield SA, et al. Plasma antioxidants, genetic variation in SOD2, CAT, GPX1, GPX4and prostate cancer survival. Cancer Epidemiol Biomarkers Prev. 2014 Apr 7. Epub ahead of print.
- Ragsdale JW 3rd, Halstater B, Martinez-Bianchi V. Prostate cancer screening. Prim Care. 2014;41(2):355-370.
- Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database Syst Rev. 2013;1:CD004720.
- Mariani S, Lionetto L, Cavallari M, et al. Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. Int J Mol Sci. 2014;15(1):1433-1440.
- Bowen P, Chen L, Stacewicz-Sapuntzakis M, et al. Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis. Exp Biol Med (Maywood). 2002;227(10):886-893.
- 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 Suppl):3486S-3492S.
- Holzapfel NP, Holzapfel BM, Champ S, Feldthusen J, Clements J, Hutmacher DW. The potential role of lycopene for the prevention and therapy of prostate cancer: from molecular mechanisms to clinical evidence. Int J Mol Sci. 2013;14(7):14620-14646.
- Chan JM, Weinberg V, Magbanua MJ, et al. Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer. Cancer Causes Control. 2011;22(1):141-150.
- Lee ST, Wong PF, Cheah SC, Mustafa MR. Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells. PLoS One. 2011;6(4): e18915.
- Lee ST, Wong PF, Hooper JD, Mustafa MR. Alpha-tomatine synergises with paclitaxel to enhance apoptosis of androgen-independent human prostate cancer PC-3 cells in vitro and in vivo. Phytomedicine. 2013;20(14):1297-1305.
- Deschasaux M, Pouchieu C, His M, Hercberg S, Latino-Martel P, Touvier M. Dietary total and insoluble fiber intakes are inversely associated with prostate cancer risk. J Nutr. 2014;144(4):504-510.
- Stacewicz-Sapuntzakis M, Borthakur G, Burns JL, Bowen PE. Correlations of dietary patterns with prostate health. Mol Nutr Food Res. 2008;52(1):114-130.