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Title:The role of tomato and lycopene consumption on prostate carcinogenesis and prostate cancer treatment
Author(s):Rowles III, Joe Lee
Director of Research:Erdman, John W
Doctoral Committee Chair(s):Jeffery, Elizabeth H
Doctoral Committee Member(s):O'Brien, William D; Bolton, Eric C; Amengual Terrasa, Jaime
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Carotenoids
lycopene
prostate cancer
prostate cancer treatment
prostate carcinogenesis
Abstract:Prostate cancer (PCa) is most commonly diagnosed cancer among men in the United States. Following PCa diagnosis, men often seek information about foods and supplements that may improve their response to therapies, quality of life and survival. Tomatoes and their primary bioactive (lycopene) are one of the most researched foods that have the potential to reduce prostate carcinogenesis. Currently, the majority of the literature has been observational epidemiological literature with inconsistent results. Although preventing PCa is preferable to treating PCa, patients seeking information about foods and supplements might already have cancer. Importantly, the prostate microenvironment is not the same prior to cancer initiation, during PCa promotion/ progression, and during treatment. As a result, we sought to clarify the epidemiological associations between tomatoes (and lycopene) and PCa incidence, and to evaluate the role of tomato feeding in an animal model that was undergoing two common treatment approaches. In Chapter 2, we evaluated the associations between tomatoes and PCa incidence. In this meta-analysis, we found that increased tomato consumption was associated with a reduced risk of PCa (RR=0.81, 95% CI =0.71-0.92, p=0.001). This finding was supported by dose-responses for several types of tomato products. In particular, it was observed that bioavailability of lycopene was important. Raw tomato consumption was not associated with a decreased risk of PCa (p=0.487), while cooked tomatoes and sauces (sources with high lycopene bioavailability) were associated with a decreased risk of PCa (p=0.029). In Chapter 3, we evaluated associations between lycopene and PCa incidence. Similar to the whole food product, increased lycopene consumption and blood concentrations were associated with a decreased risk of PCa. These associations were also supported by dose-response associations. From the dietary meta-analysis in Chapter 2, there was an estimated 9% reduced risk for 100 grams/week of cooked tomato. For an equivalent dose of lycopene (22 mg lycopene in 100 grams of tomato puree according to the USDA Nutrient Database), tomatoes were more effective than lycopene at reducing PCa risk (9% compared to 1.6%). The greater benefit from tomato products may be due to interactions between potentially beneficial bioactive compounds in tomatoes. These meta-analyses support the hypothesis that tomato products or lycopene reduce prostate carcinogenesis. In Chapter 4, we aimed to determine whether dietary lyophilized tomato powder (TP) or lycopene would be capable of affecting the growth of castration-resistant prostate cancer (CRPC). This aggressive and often lethal stage of PCa occurs after the prostate tumor acquires mutations to sustain growth despite androgen deprivation therapy (ADT). We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. To test this hypothesis, TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice were castrated at 12-13 weeks of age to model ADT, and the emergence of CRPC was monitored by ultrasound in two studies. In Study 1, TRAMP mice (n=80) were weaned onto an AIN-93G-based control diet (Con-L, n=28), a 10% TP diet (TP-L, 10% lyophilized w/w, n=26), or a control diet followed by a TP diet after castration (TP-Int1, n=26). In Study 2, TRAMP mice (n=85) were randomized onto a control diet with placebo beadlets (Con-Int, n=29), a tomato diet with placebo beadlets (TP-Int2, n=29) or a control diet with lycopene beadlets (Lyc-Int, n=27) following castration (12 weeks of age). Tumor incidence and growth were monitored by ultrasound beginning at 10 weeks of age. Mice were euthanized 4 weeks after tumor detection or at 30 weeks of age if no tumor was detected. In contrast to studies of de novo carcinogenesis in multiple pre-clinical models, tomato components following castration did not reduce CRPC incidence, time to tumor detection or final tumor weight. In Chapter 5, we hypothesized that dietary TP would not reduce apoptosis or cell death within the prostate tumor following external beam radiation therapy (EBRT) and would protect surrounding tissues from radiation-induced damage. Tomatoes contain carotenoids and other potent antioxidants. To evaluate this hypothesis, we conducted a pilot and dietary study. In the pilot study, male TRAMP mice (n=18) were provided a powdered AIN-93G diet. In the Diet study, male TRAMP mice (n=76) were provided a control diet or a modified AIN-93G diet containing 10% TP (w/w) beginning at 4 weeks of age. In both studies, prostates were monitored by ultrasound for in vivo tumor detection and 3-D volumetric measurement biweekly. Once tumors reached a volume of 1000 mm3 or at 24 weeks of age, the caudal half of the mouse was irradiated with 7.5 gy (Rad) or 0 gy (sham) with a Cobalt-60 source. In the pilot study, mice were euthanized after 0, 24, or 72 hours. Based on the results of the pilot study, mice in the main Diet study were euthanized 24 hours after radiation or sham treatment. Within the Diet study, prostate tumor scores for apoptosis and necrosis were not modified by tomato consumption; however, tomato consumption did not reduce acute changes in radiation-induced inflammation or damage within the prostate and surrounding tissues. In conclusion, this work has revealed consistent associations between tomato products or lycopene and risk of prostate cancer incidence within published epidemiological studies. In our preclinical studies of tomato products and PCa treatments (ADT and EBRT), it was found that the responses to treatment were not modified by a diet containing 10% TP or lycopene. While further work in animal models and humans are needed, it is notable that these are the first studies to evaluate the interactions between tomato products on PCa treatments. Data from these epidemiological and preclinical studies highlight the importance of healthy dietary patterns throughout the lifespan. These data are very important for patients that are diagnosed with PCa and seek out information about the types of foods or supplements that can improve their clinical outcomes. Further studies should evaluate differences within the tumor microenvironment to determine if tomato products are more effective for specific subtypes or specific clonal populations of PCa. Additional epidemiological studies are also needed to determine if circulating lycopene concentrations are associated with specific stages of PCa and treatment-associated outcomes (such as biochemical recurrence and cachexia). In summary, this dissertation has contributed novel findings to our understanding of the interactions between tomato products and PCa.
Issue Date:2020-05-08
Type:Thesis
URI:http://hdl.handle.net/2142/107997
Rights Information:Copyright 2020 Joe Lee Rowles III
Date Available in IDEALS:2020-08-26
Date Deposited:2020-05


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