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Title:Impact of dietary tomato intake on prostate cancer throughout the course of disease development and progression in a transgenic mouse model
Author(s):Applegate, Catherine Christine
Director of Research:Erdman, John W
Doctoral Committee Chair(s):Madak-Erdogen, Zeynep
Doctoral Committee Member(s):Dobrucki, Wawrzyniec L; Nakamura, Manabu T; 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):prostate cancer
tomato
TRAMP
mouse
Abstract:Despite decreasing trends of overall diagnosis, prostate cancer (PCa) is the most commonly diagnosed male cancer in the United States. However, the decrease in total and early stage PCa masks the disproportionate increased trend in the incidence of advanced stage disease. Interestingly, evidence has shown that overweight and obesity, an affliction affecting nearly 80% of adult males in the United States, increases the risk for advanced PCa. The standard treatment for advanced or metastatic PCa involves pharmacological depletion of growth-stimulating hormones by androgen deprivation therapy (ADT). Despite initial tumor regression, PCa inevitably recurs within 2-3 years and becomes known as castration-resistant PCa (CRPC), a terminal and treatment-resistant disease. Second only to potatoes, tomatoes are widely consumed in a variety of forms throughout the United States. Abundant epidemiological and pre-clinical evidence exists to show that physiologically relevant levels of dietary tomato intake reduce the risk for primary PCa, but a gap in knowledge exists regarding a potential role for tomato in protecting against the emergence of CRPC or the increased risk of advanced PCa with overweight/obesity. In Chapter 1, I conducted a literature review to provide an in-depth background regarding prostate physiology, PCa development and progression, PCa treatment, and the emergence of CRPC and treatment-resistant disease. I also included a review of the current pool of literature reporting outcomes of tomato and tomato carotenoids on risks and mechanisms associated with PCa. In Chapter 2, we aimed to investigate whether dietary lyophilized tomato powder (TP) or lycopene impacted the molecular expression of castrate-resistant tumors. In two independent studies using ultrasound imaging to monitor in vivo tumor growth, we previously showed that neither dietary tomato nor supplementation of its primary bioactive, lycopene, inhibited the emergence or reduced the growth of CRPC in a mouse model of PCa (transgenic adenocarcinoma of the mouse prostate; TRAMP), castrated to mimic ADT. In this chapter, we aimed to investigate the molecular underpinnings of individual CRPC tumors with the hypothesis that dietary tomato or lycopene supplementation impacted the expression of biomarkers associated with aggressive tumors. As a secondary analysis, we also sought to identify common variables between seemingly heterogeneous CRPC tumors that could provide insight into the molecular determinants of potentially diet-dependent and diet-independent effects of CRPC variants on tumor growth. Immunohistochemical results showed phenotypic variation of TRAMP tumors similar to that described in human tumors (mixed androgen-sensitive and androgen-resistant phenotypes), and divergent growth patterns between individual TRAMP tumors was evident. Molecular analyses revealed heterogeneity of protein and gene expression between diets and across animals from both studies, with TP dietary interventions reducing the expression of molecular markers associated with androgen signaling (AR) and inflammation (IL-6, pSTAT3-Y705). No effects were observed by lycopene supplementation. Between tumor phenotypes, there was differential expression of genes related to androgen signaling (srd5a1, srd5a2) and angiogenesis (vegfa). In Chapter 3, we hypothesized that a “Western”-style diet (high in both fat and sugar) would induce weight gain and subsequently promote tumor growth in TRAMP mice. In addition, we hypothesized that dietary tomato would attenuate the carcinogenic effects of diet and obesity on PCa development and progression. Four-week-old TRAMP mice were randomly assigned to consume one of four diets (n=45/diet): control (CON) or obesogenic (OB), both with and without 10% TP. Prostate tumor incidence and growth were monitored via ultrasound imaging. Mice were terminated one (W1) or four (W4) weeks following tumor development to assess early and later molecular changes associated with inflammation and angiogenesis in tumors. Regardless of TP, OB diets led to greater body weight over time, greater tumor incidence, earlier age at tumor onset, higher body weight at tumor detection, and greater post-mortem periprostatic adipose weight. TP did not affect tumor development in lean animals (CON diets), but TP was associated with a 130% reduction in PCa risk when incorporated into the OB diet. After controlling for diets, weight gain from randomization to time of tumor detection was proportionate to an increased PCa risk (each 1 g increase in body weight was associated with a 9% increased risk for tumor development; proportionally, each 5 g/m2 body mass index increase in men is associated with an 8% increased risk for advanced PCa) and larger tumor volumes over time. There were no differences between diets for tumor volume at detection, tumor growth rate, or tumor weight at euthanasia. TP inclusion in CON and OB diets reduced in vivo tumor blood perfusion over time compared with blood perfusion of tumors from non-TP-fed animals, measured by ultrasound microvessel imaging techniques. Immunohistochemical analysis of tumor sections showed that OB diets were associated with increased irregularity of blood vessel lumens, and that the inclusion of TP in the OB diet led to improvements in lumen regularity scores. Intratumoral inflammatory markers (leptin, IL-6, pSTAT3-Y705) were not significantly increased by OB diets, but TP led to reductions in IL-6 and pSTAT3-Y705 over time. This work has demonstrated that tomato consistently interacts with the prostate tumor microenvironment, but the magnitude of effect may be dependent on stage of tumor progression. Chapter 2 results suggested a minor role for TP in reducing the expression of growth-promoting molecules in CRPC, which has the potential to translate to clinical significance over time. Chapter 3 demonstrated that both Western-modeled diets and weight gain induced by these diets was associated with greater PCa risk at a rate proportionate to the increased risk of developing advanced PCa by weight seen in humans. Moreover, this increased risk by obesogenic diets and weight gain was attenuated by 10% TP. Marginal effects were observed by TP reduction of markers of angiogenesis and inflammation; however, we conclude that further exploration of alternative mechanisms contributing to the pro-tumorigenic effects of obesity on PCa development and progression are necessary. Data from these studies therefore suggest a potential role for tomato intake in the reducing the risk of PCa, especially within current American dietary patterns and sedentary habits that promote obesity. A more modest effect by TP was demonstrated in CRPC tumors, encouraging healthy dietary patterns that include tomatoes throughout cancer treatments to maximize potential adjuvant effects. Ongoing work is exploring the impact of TP on in vivo measurements of prostate tumor metabolism and angiogenesis, and further studies should evaluate additional differences within the tumor microenvironment using high-throughput analysis techniques to identify at which point(s) TP interacts with which pathway(s). In summary, this dissertation has contributed novel findings to previously unexplored effects of tomato on different stages of PCa.
Issue Date:2020-07-13
Type:Thesis
URI:http://hdl.handle.net/2142/108596
Rights Information:Copyright 2020 Catherine Applegate
Date Available in IDEALS:2020-10-07
Date Deposited:2020-08


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