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Title:Reducing the risk of prostate cancer with tomato and soy bioactives
Author(s):Conlon, Lauren E
Director of Research:Erdman, John, Jr.
Doctoral Committee Chair(s):Helferich, William G.
Doctoral Committee Member(s):Chen, Hong; Wallig, Matthew A.
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):tomato
soy
prostate
cancer
transgenic adenocarcinoma mouse prostate (TRAMP)
coconut
gerbil
intervention
diet
daidzein
equol
lycopene
Abstract:Prostate cancer (PCa) is the second leading cause of cancer and cancer-related deaths in U.S. men. Dietary strategies to prevent or reduce PCa would have a significant impact on public health. The American Institute for Cancer Research (AICR) recommends consuming a variety of fruits, vegetables, whole grains, and legumes for cancer prevention. Specifically, epidemiological studies suggest that consumption of tomato or soy products may reduce the risk of PCa. Tomatoes contain many bioactive components, but the tomato carotenoids, lycopene, β-carotene, phytoene, and phytofluene, receive much of the attention regarding PCa incidence. As tomato carotenoids are lipophilic, strategies to enhance absorption and tissue distribution have been of interest. Evidence suggests that co-consumption of tomato carotenoids with a source of dietary fat increases their absorption and bioavailability, however, the influence of fat type on tomato carotenoid tissue accumulation has not been well understood. Therefore, we fed Mongolian gerbils (Meriones unguiculatus) a 20% fat diet containing 10% tomato powder (TP) and either safflower oil (polyunsaturated fat) or coconut oil (saturated fat) and determined the influence of dietary fat type on tissue carotenoid bioaccumulation. Coconut oil fed-gerbils had increased tissue carotenoid concentrations including total carotenoids in the serum (p=0.0003), adrenal glandular phytoene (p=0.04), hepatic phytofluene (p=0.0001), testicular all-trans lycopene (p=0.01), and cis-lycopene (p=0.006) in the prostate-seminal vesicle complex compared to safflower oil. Safflower oil-fed gerbils had greater splenic lycopene concentrations (p=0.006) compared to coconut oil-fed gerbils. Additionally, coconut oil feeding increased serum cholesterol (p=0.0001), and decreased hepatic cholesterol (p=0.0003) compared to safflower oil. Coconut oil enhanced tissue uptake of tomato carotenoids to a greater degree than safflower oil, and these results may have been due to the large proportion of medium chain fatty acids in coconut oil which might have caused a shift in cholesterol flux to favor extrahepatic carotenoid tissue deposition. In vivo studies examining the effect of TP or tomato paste on PCa have demonstrated mostly positive results. However, these studies often model lifelong consumption of tomato products (initiated post-weaning, ~4 weeks of age) and may not accurately reflect the changes in dietary patterns or supplement use in men newly diagnosed with PCa. Therefore, we designed a 10% TP diet intervention in TRAMP mice to determine the effects of consuming TP (post-puberty, ~5-6 weeks of age) during the process of carcinogenesis on PCa incidence. 8-week-old male C57BL/6 X FVB TRAMP mice were randomized to consume either an AIN-93G + 10% TP diet (N=90) or the AIN-93G control diet (N=88) and assigned to one of three sacrifice ages: 12 (N=59), 16 (N=60), or 20 (N=59) weeks. Overall cancer incidence was not impacted by diet at any time point. However, at 16 weeks of age, TP significantly increased high-grade PIN (HGP) (p=0.014) and significantly decreased poorly-differentiated (PD) (p=0.024) lesions compared to the control diet suggesting a modest reduction in cancer progression by TP at 16 weeks of age. There are two variables that may explain the modest effect of TP in this study: the low amount of lycopene in the TP diet and the timing of the dietary intervention. The TP diet contained 30-fold less lycopene than a previous study in our lab. However, after 8 and 12 weeks of feeding, mice accumulated similar tissue concentrations of carotenoids in their serum, gonadal adipose, and prostate suggesting that the amount of carotenoids in the diet may not have been the critical factor since tissue levels of lycopene appear to become saturated with long-term feeding. Rather, the initiation of the diet intervention at 8 weeks of age instead of 4 weeks of age may have been too late in cancer development to substantially impact carcinogenesis, as studies have shown prostate-specific gene expression changes as early as 8-10 weeks of age in TRAMP mice. We histopathologically confirmed that mice had low-grade and moderate-grade PIN at 8 weeks of age, when the dietary intervention was initiated. The TRAMP model is an aggressive model of PCa, therefore, diet may not be able to have as great of an impact when initiated after puberty (~6 weeks of age) when PCa is developing rapidly in this model. Both the late intervention time combined with low levels of carotenoids in the TP diet may have contributed to the lack of an overall effect. This study re-emphasizes the importance of lifelong consumption of TP for PCa prevention. Epidemiological studies have also associated soy consumption with a decreased risk of PCa. One hypothesis for the decreased risk of PCa by soy consumption is the production of the microbial-metabolite, equol, from daidzein. A TRAMP study from our lab suggested that a 2% soy germ diet reduced PCa incidence by 34%. The same study observed that prostatic equol concentrations were 39 times greater than prostatic genistein and 3 times higher than prostatic daidzein suggesting that equol may have been a significant factor in reducing PCa incidence. We aimed to determine if equol was responsible for the protective effect of soy germ by replicating that study with additional dietary groups. 3-week old male C57BL/6 X FVB TRAMP mice were weaned from our breeding colony and immediately acclimated to an AIN-93G control diet for one week. At 4 weeks of age, mice (n=30 per diet group) were randomized to one of four pelleted study diets, AIN-93G control, AIN-93G + 2% soy germ, AIN-93G + 92 ppm daidzein, or AIN-93G + 88 ppm equol until 18 weeks of age. To our surprise, we did not detect any statistical differences in cancer incidence between diets. In the previous study, we observed a 100% cancer incidence in TRAMP mice fed a control diet until 18 weeks of age, however, the control group in this study only had a 24% incidence in cancer at 18 weeks of age. Additionally, mice in the current study had less food intake and significantly decreased body weights (p<0.001) compared to those in the previous study. A reduction in food intake and body weight is known to reduce cancer incidence in a number of animal models and is likely to have contributed to the decrease in expected cancer incidence in the current study. We hypothesize that the reason for the decreased food intake, the decreased body weight, and decreased cancer incidence was due to the physical format of the study diets. Mice in the current study were fed pelleted diets, whereas mice in the previous study were fed powdered diets. Differences between powdered and pelleted diets exist and have been shown to influence obesity which, in turn, can affect cancer development. Additionally, we measured serum levels of cytokines in mice with tumors and in mice with high-grade PIN. In mice with tumors, daidzein and equol diets significantly altered the levels of IL-1β, IL-10, IFN-γ, and TNF-α compared to the control and soy germ groups suggesting that daidzein and equol may play a role in moderating systemic inflammation in advanced PCa. While our diets did not impact overall cancer incidence in this study, the role of daidzein and equol in PCa still warrants investigation. Overall our findings suggest that consuming fruits and vegetables containing bioactives such as carotenoids or isoflavones may be beneficial in reducing PCa incidence. The co-consumption of fat with carotenoids can increase their bioavailability and tissue biodistribution. Lifelong consumption of carotenoid-containing fruits and vegetables is likely more protective than changes to the diet or supplement use at the time of cancer diagnosis. Lastly, the format of the diet is important to consider when studying the effects of bioactives in cancer models. Nonetheless, dietary strategies to reduce the risk of PCa remain of interest and of public health significance.
Issue Date:2015-05-28
Type:Thesis
URI:http://hdl.handle.net/2142/88136
Rights Information:Copyright 2015 Lauren Elizabeth Conlon
Date Available in IDEALS:2015-09-29
Date Deposited:August 201


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