Prostate Carcinogenesis Research Articles

Inflammatory and Insulinemic Dietary Patterns: Influence on Circulating Biomarkers and Prostate Cancer Risk

Prostate cancer is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. In the Prostate, Lung, Colorectal, and Ovarian cancer cohort, we calculated the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores from food frequency questionnaire data among 3,517 men and women who provided a blood sample at enrollment. We used these scores in multivariable-adjusted linear regression to validate EDIH and EDIP against relevant circulating biomarkers. In a separate sample of 49,317 men, we used multivariable-adjusted Cox regression to evaluate associations of EDIH and EDIP with prostate cancer (total and subtypes) risk. Participants consuming the most hyperinsulinemic diets (EDIH quintile 5) had significantly higher concentrations of C-peptide, insulin, c-reactive protein, TNFα-R2, and lower adiponectin, than those in quintile 1. Similarly, participants consuming the most proinflammatory diets had significantly higher concentrations of IL6, TNFα-R2, C-peptide, insulin, and lower adiponectin. Men consuming hyperinsulinemic diets were at higher total prostate cancer risk: HRquintile5vs1, 1.11; 95% confidence interval (CI), 1.01-1.23; P trend = 0.03, especially high-grade cancer: HRquintile5vs1, 1.18; 95% CI, 1.02-1.37; P trend = 0.06. The EDIP was not associated with prostate cancer risk. In summary, EDIH and EDIP predicted concentrations of known insulinemic and inflammatory biomarkers, and EDIH further predicted risk of future prostate cancer. Interventions to reduce the adverse role of hyperinsulinemic diets may be a means of prostate cancer prevention.

β2 -adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog-Gli1 signaling activation.

BackgroundConsiderable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown.MethodsThe expression level of β2‐adrenergic receptor (β2‐AR) in tissue microarray was evaluated by immunohistochemistry. The effects of isoproterenol (ISO) or Sonic Hedgehog (Shh) signaling inhibitor on tumor growth were analyzed in proliferation and colony formation assays. The apoptosis of cells was analyzed by flow cytometry. Small hairpin RNA‐based knockdown of β2‐AR or Gli1 was validated by Western blot analysis and real‐time PCR. Effects of β2‐AR on prostate carcinogenesis in vivo were observed in a mouse xenograft model. The expression levels of the indicated proteins in xenograft tissues were evaluated by immunohistochemistry. Expression levels of Shh signaling components and downstream proteins were assessed by immunoblotting.ResultsWe determined that β2‐AR was expressed at significantly higher levels in carcinoma than in normal prostate tissues. β2‐AR signaling also played an essential role in sustaining PCa cell proliferation in vivo and in vitro. We also found that inhibition of Shh signaling or knockdown of Gli1 expression significantly restrained ISO‐induced cell proliferation in vitro. ISO alleviated the apoptosis induced by suppressing or knocking down of Gli1. The β2‐AR agonist ISO upregulated the transcription and protein expression of target genes of Shh signaling, including c‐Myc, Cyclin D1, and VEGFA. Conversely, knocking down β2‐AR markedly suppressed the expression of Shh components in vivo and in vitro. In Gli1 knockdown cells, ISO failed to increase the expression of target genes of Shh signaling.ConclusionsIn this study, we uncovered an important role of β2‐AR signaling in regulating the Shh pathway activity in PCa tumorigenesis and provide further insight into the mechanism of the involvement of the Hh signaling pathway. Furthermore, given the efficacy of β2‐adrenergic modulation on PCa, our study might also add evidence for potential therapeutic options of β‐blockers for PCa.

Fetuin B overexpression suppresses proliferation, migration, and invasion in prostate cancer by inhibiting the PI3K/AKT signaling pathway

Fetuin B (FETUB) is a glycoprotein that is a member of the cysteine protease inhibitor family, and it is associated with cancer. However, the role of FETUB in prostate carcinogenesis is unknown. In this study, we overexpressed FETUB in prostate cancer cells by using lentivirus and then studied the impacts on cell apoptosis, migration and invasion. We found that apoptosis was increased and the migration and invasion of prostate cancer cells were significantly inhibited after overexpression. Then, we performed experiments in vivo and found that there were fewer tumors in the overexpression groups than in the control groups. In addition, we demonstrated that overexpression of FETUB inactivates the PI3K/AKT signaling pathway. Rescue assays revealed that intervention of 740Y-P reversed the anti-tumor effect of FETUB on prostate cancer cells. Taken together, our results revealed that FETUB may act as a novel regulator to promote apoptosis and inhibit the migration and invasion of prostate cancer cells and that FETUB is related to the inactivation of the PI3K/AKT signaling pathway.

Xanthine Oxidase/Dehydrogenase Activity as a Source of Oxidative Stress in Prostate Cancer Tissue

Prostate cancer (PC) is one of the most frequent malignancies. Better biomarkers are constantly wanted, such as those which can help with the prediction of cancer behavior. What is also needed is a marker which may serve as a possible therapeutic target. Oxidative stress (OS), which is a hallmark of cancer, is included in the pathogenesis and progression of PC. We have conducted the present study to determine whether xanthine oxidase/dehydrogenase activity is the source of OS in prostate tissue. We have also determined the concentration of TBA-reactive substances (TBARS) and advanced oxidation protein products (AOPP), as well as the activity of catalase. Xanthine oxidase (XO) activity is significantly higher (p < 0.001) in tumor tissue when compared to the control healthy tissue. The concentration of TBARS (p < 0.001) and AOPP (p < 0.05) are also higher in tumor tissue. Catalase has raised its activity (p < 0.05) versus the control. There is also a strong correlation between XO activity and prostate-specific antigen (PSA) levels in the serum. These results indicate a significant role of XO activity in OS in prostate carcinogenesis, and it could be a possible theranostic biomarker, which can be important for a better understanding of the disease, its evolution, and prognosis. A promising treatment may be using XO inhibitors such as allopurinol as adjuvant therapy.

Abstract 1146: Development of CRISPR human Skp2 knock-in in the prostate of mouse and the associated prostate organoids for testing Skp2 targeting agents

Abstract S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten or p53 deficient mice. We therefore have aimed to establish CRISPR human Skp2 (hSkp2) knock-in in the prostate of mouse to examine its role in prostate carcinogenesis. In addition, Skp2 overexpressing organoids are being developed for convenient and efficient screening of specific Skp2 inhibitors. cDNA of hSkp2 and porcine teschovirus-1 (P2A) was introduced into immediate upstream of mouse probasin coding sequencing using CRISPR knock-in targeting approach to establish transgenic mice specifically overexpressing hSkp2 in the prostate glands. Quantitative PCR, western blot and immunohistochemistry (IHC) were used to identify the expression levels of Skp2 and histopathological analyses were performed after H&amp;E staining. Prostate glands were dissected and digested for organoid culture, then morphological features and viability of organoids were evaluated following treatments of potential Skp2 inhibitors. Prostate glands and other tissues from mice of three transgenic lines which were genotyped positive were dissected and hSkp2 was detected in ventral, dorsal and lateral prostate lobes, but not in testis, kidney, spleen, and liver. Line 10092 was found to have the highest expression of hSkp2 among these three lines. Prostate weight slightly increased in transgenic mice compared to that of wild-type control mice. Hyperplasia, prostatic intraepithelial neoplasia (PIN), and carcinoma were noted, which suggested that overexpression of hSkp2 in the prostate of mice promoted proliferation and prostate tumorigenesis. Organoids that were derived from the prostate of hSkp2 transgenic mice recapitulated prostatic phenotypic features and maintained a high level of hSkp2. A novel Flavokawain A derivative was found to selectively alter the morphology of hSkp2 organoids and decrease the viability. Prostatic lesions found in the hSkp2 knock-in mice demonstrated a potential role of hSkp2 in early prostate carcinogenesis and organoids overexpressing hSkp2 have the utility for screening out compounds targeting Skp2 in prostate cancer. Citation Format: Liankun Song, Shan Xu, Kia Arabzadehkaffash, Ali Fazelpour, Dongjun Fu, Matthew Tippin, Xiaolin Zi. Development of CRISPR human Skp2 knock-in in the prostate of mouse and the associated prostate organoids for testing Skp2 targeting agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1146.

Oncogenic transformation of human benign prostate hyperplasia with chronic cadmium exposure

Experimentally, it has been proved that cadmium served as an effective carcinogen and able to induce tumors in rodents in a dose-specific manner. However, systemic evaluation of cadmium exposure for the transformation of prostatic hyperplasia into prostate cancer (PCa) is still unclear. In the present study, an attempt has been made to establish cadmium-induced human prostate carcinogenesis using an in vitro model of BPH cells. Wide range of cadmium concentrations, i.e., 1 nM, 10 nM, 100 nM and 1μM, were chronically exposed to the human BPH cells for transformation into PCa and monitored using cell and molecular biology approaches. After eight weeks of exposure, the cells showed subtle morphological changes and shifts of cell cycle in the G2M phase. Significant increase in expression of prostatic genes AR, PSA, ER-β, and 5αR with increased nuclear localization of AR and pluripotency markers Cmyc, Klf4 indicated the carcinogenic effect of Cd. Further, the BPH cells exposed to Cd showed a substantial increase in the secretion of MMP-2 and MMP-9, influencing migratory potential of the cells along with decreased expression of the p63 protein which further strengthen the progression towards carcinogenesis and aggressive tumor studies. Data from the present study state that Cd exhibited marked invasiveness in BPH cells. These observations established a connecting link of BPH towards PCa pathogenesis. Further, the study will also help in investigating the intricate pathways involved in cancer progression.

Prostate Carcinogenesis: Insights in Relation to Epigenetics and Inflammation.

Prostate cancer is a multifactorial disease that mainly occurs due to the accumulation of somatic, genetic, and epigenetic changes, resulting in the inactivation of tumor-suppressor genes and activation of oncogenes. Mutations in genes, specifically those that control cell growth and division or the repair of damaged DNA, make the cells grow and divide uncontrollably to form a tumor. The risk of developing prostate cancer depends upon the gene that has undergone the mutation. Identifying such genetic risk factors for prostate cancer poses a challenge for the researchers. Besides genetic mutations, many epigenetic alterations, including DNA methylation, histone modifications (methylation, acetylation, ubiquitylation, sumoylation, and phosphorylation) nucleosomal remodeling, and chromosomal looping, have significantly contributed to the onset of prostate cancer as well as the prognosis, diagnosis, and treatment of prostate cancer. Chronic inflammation also plays a major role in the onset and progression of human cancer, via modifications in the tumor microenvironment by initiating epithelialmesenchymal transition and remodeling the extracellular matrix. In this article, the authors present a brief history of the mechanisms and potential links between the genetic aberrations, epigenetic changes, inflammation, and inflammasomes that are known to contribute to the prognosis of prostate cancer. Furthermore, the authors examine and discuss the clinical potential of prostate carcinogenesis in relation to epigenetics and inflammation for its diagnosis and treatment..

The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis.

M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P < 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease.

Dietary Tomato or Lycopene Do Not Reduce Castration-Resistant Prostate Cancer Progression in a Murine Model

Dietary tomato products or lycopene protect against prostate carcinogenesis, but their impact on the emergence of castration-resistant prostate cancer (CRPC) is unknown. We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12-13 wk and the emergence of CRPC was monitored by ultrasound in each study. In Study 1, TRAMP mice (n=80) were weaned onto an AIN-93G-based control diet (Con-L, n=28), a 10% tomato powder diet (TP-L, 10% lyophilized w/w, n=26), or a control diet followed by a tomato powder 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 (aged 12 wk). Tumor incidence and growth were monitored by ultrasound beginning at an age of 10 wk. Mice were euthanized 4 wk after tumor detection or aged 30 wk if no tumor was detected. Tissue weights were compared by ANOVA followed by Dunnett's test. Tumor volumes were compared using generalized linear mixed model regression. Ultrasound estimates for the in vivo tumor volume were strongly correlated with tumor weight at necropsy (R2=0.75 and 0.94, P <0.001 for both Studies 1 and 2, respectively). Dietary treatments after castration did not significantly impact cancer incidence, time to tumor detection, or final tumor weight. In contrast to studies of de novo carcinogenesis in multiple preclinical models, tomato components had no significant impact on the emergence of CRPC in the TRAMP model. It is possible that specific mutant subclones of prostate cancer may continue to show some antiproliferative response to tomato components, but further studies are needed to confirm this.

Abstract IA12: Role of endocrine disruptors in cancer development

Abstract Multiple lines of evidence show that brief, early-life exposures to bisphenol A (BPA) can increase the risk of prostate cancer (PCa) with aging. Initial work from our laboratory determined that low-dose BPA exposure during rat development reprograms the prostate and enhances incidence and severity of neoplastic lesions (PIN) in response to elevated adult estrogen levels, as occurs in aging men (Prins et al., Repro Tox 2007). Subsequent BPA dose-response studies revealed that elevated carcinogenic risk is found at doses that yield undetectable serum free-BPA with documented PIN progression to PCa (Prins et al., EHP 2017). Epigenetic modifications (altered DNA and histone methylation) provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. Our studies within the CLARITY-BPA Consortium, a collaboration with the NIEHS, NTP, and FDA, found that continuous low-dose BPA exposure from fetal life to 6 months altered adult dorsal prostate stem cell homeostasis, increased stem cell numbers and progenitor cell proliferation, and shifted lineage commitment to favor basal progenitor cells (Prins et al., EHP 2018). At 1 year, dorsolateral prostate ducts had heightened multiplicity of estrogen-driven adenocarcinoma as a function of chronic BPA exposure (2.5 μg/kg/day). We propose that the BPA-induced stem cell alterations may underpin increased carcinogenic risk with aging. To provide translational evidence for human exposures, two approaches were used. First, we generated a pioneer in vitro model of directed differentiation of hESC into prostatic organoids. Exposure to 1-10 nM BPA resulted in focal clusters of stem cells within the organoids, a phenotype not observed in controls, which suggests aberrant stem-cell self-renewal (Calderon and Prins, PLOS One 2015). Next, we developed in vitro and in vivo models utilizing primary prostate cells from young, disease-free organ donors. BPA exposure to 3-D human prostasphere cultures increased stem-progenitor cell self-renewal and stem-related gene expression through membrane-initiated ER signaling pathways. Tissue-cell recombination of human prostasphere cells and rat UGM with renal grafting into nude mice was used as an in vivo model to assess carcinogenicity (Prins et al., Endocrinol 2014). Developmental BPA exposure combined with adult estradiol led to a heightened PIN/PCa incidence (33-46%) in the human prostate epithelium of the chimeric prostate tissue compared to oil controls given adult estrogen (13%; P&amp;lt;0.01). Together, these findings indicate that stem and progenitor cells may be direct BPA targets and suggest that humans may be susceptible to endocrine-disrupting chemical (EDC)-imprinted prostate disease in a manner similar to the rodent models. Supported by NIH grants ES015584, ES018748, ES020886, ES027792, CA172220. Citation Format: Gail S. Prins. Role of endocrine disruptors in cancer development [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA12.

Investigation of spectroscopic and proteomic alterations underlying prostate carcinogenesis

Prostate cancer (PCa) treatment remains challenging, especially in advanced stages, where the lack of sensitivity and specificity of available biomarkers makes it difficult to establish an accurate prognosis. Therefore, it is imperative to study PCa biology to identify key molecules that can improve PCa management. In this study, eight prostate tumor tissues and paired normal tissues were analyzed using two approaches—Fourier-transform infrared (FT-IR) spectroscopy for spectroscopic profiling of biomolecules and antibody microarray for signaling proteins—with the main goal of identifying metabolic and proteomic changes that enable the distinction between normal and tumor conditions. Principal component analysis of FT-IR spectra revealed different spectroscopic signals for each condition. The most relevant changes in prostate tumor tissues identified by FT-IR were dysregulation in lipid metabolism, lower polysaccharide and glycogen content, higher nucleic acid content, and increased protein phosphorylation. Using an antibody microarray, 42 proteins were identified as differentially regulated between the two conditions; 14 of those revealed changes in their phosphorylation status. These proteins include transcription factors and kinases and constitute a highly-interconnected interaction network. Altogether, our data reveal metabolic and proteomic alterations that may be of interest in future translational studies aimed at establishing PCa prognosis and treatment. SignificanceProstate tumor tissues and adjacent benign tissues were analyzed using two approaches—Fourier-transform infrared (FT-IR) spectroscopy for biomolecules and an antibody microarray for signaling proteins, which allowed to identify a panel of metabolic and proteomic alterations that may be of interest in future translational studies to enable the distinction between normal and tumor conditions.

Evaluation of Notch1 gene expression in prostate carcinoma

Aim: Prostate cancer is one of the most common cancers in the world and its incidence is rapidly increasing. Currently, several new treatment strategies that target specific signaling pathways as well as immunotherapy are being explored for prostate cancer. In the current study, we aimed to investigate the frequency and clinicopathologic features associated with Notch1 gene expression using immunohistochemistry and real-time-polymerase chain reaction in patients with prostate cancer. Methods: This research was planned as a cohort study. Tissue samples of 60 patients with prostate cancer and 20 patients with benign prostatic hyperplasia were selected from the archives. Twenty patients with benign prostatic hyperplasia were used as the control group. The relative expression levels of Notch1 gene were determined by real-time-polymerase chain reaction while Notch1 protein expression was analyzed using immunohistochemistry. Results: We found Notch1 gene expression at a significant level in 17 (28.3%) of 60 patients with prostate carcinoma. We found a significant correlation between high Gleason scores (P=0.007), high ISUP (International Society of Urologic Pathologists) grade group scores (P=0.008) and high prostate-specific antigen levels (P=0.018) for Notch1 gene expression. Conclusions: We conclude that Notch1 is important in prostate carcinogenesis. Therefore, determining Notch1 will be an essential step in targeted therapies in patients with prostate carcinoma.

Prostate carcinogenesis: inflammatory storms.

Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.

Shaping Chromatin States in Prostate Cancer by Pioneer Transcription Factors.

The androgen receptor (AR) is a critical therapeutic target in prostate cancer that responds to antagonists in primary disease, but inevitably becomes reactivated, signaling onset of the lethal castration-resistant prostate cancer (CRPC) stage. Epigenomic investigation of the chromatin environment and interacting partners required for AR transcriptional activity has uncovered three pioneer factors that open up chromatin and facilitate AR-driven transcriptional programs. FOXA1, HOXB13, and GATA2 are required for normal AR transcription in prostate epithelial development and for oncogenic AR transcription during prostate carcinogenesis. AR signaling is dependent upon these three pioneer factors both before and after the clinical transition from treatable androgen-dependent disease to untreatable CRPC. Agents targeting their respective DNA binding or downstream chromatin-remodeling events have shown promise in preclinical studies of CRPC. AR-independent functions of FOXA1, HOXB13, and GATA2 are emerging as well. While all three pioneer factors exert effects that promote carcinogenesis, some of their functions may inhibit certain stages of prostate cancer progression. In all, these pioneer factors represent some of the most promising potential therapeutic targets to emerge thus far from the study of the prostate cancer epigenome.

Effects of Inorganic Arsenic on Human Prostate Stem-Progenitor Cell Transformation, Autophagic Flux Blockade, and NRF2 Pathway Activation.

Background:Inorganic arsenic (iAs) is an environmental toxicant associated with an increased risk of prostate cancer in chronically exposed populations worldwide. However, the biological mechanisms underlying iAs-induced prostate carcinogenesis remain unclear.Objectives:We studied how iAs affects normal human prostate stem-progenitor cells (PrSPCs) and drives transformation and interrogated the molecular mechanisms involved.Methods:PrSPCs were enriched by spheroid culture from normal human primary or immortalized prostate epithelial cells, and their differentiation capability was evaluated by organoid culture. Microarray analysis was conducted to identify iAs-dysregulated genes, and lentiviral infection was used for stable manipulation of identified genes. Soft agar colony growth assays were applied to examine iAs-induced transformation. For in vivo study, PrSPCs mixed with rat urogenital sinus mesenchyme were grafted under the renal capsule of nude mice to generate prostatelike tissues, and mice were exposed to () iAs in drinking water for 3 months.Results:Low-dose iAs () disturbed PrSPC homeostasis in vitro, leading to increased self-renewal and suppressed differentiation. Transcriptomic analysis indicated that iAs activated oncogenic pathways in PrSPCs, including the KEAP1-NRF2 pathway. Further, iAs-exposed proliferative progenitor cells exhibited NRF2 pathway activation that was sustained in their progeny cells. Knockdown of NRF2 inhibited spheroid formation by driving PrSPC differentiation, whereas its activation enhanced spheroid growth. Importantly, iAs-induced transformation was suppressed by NRF2 knockdown. Mechanistically, iAs suppressed Vacuolar ATPase subunit VMA5 expression, impairing lysosome acidification and inhibiting autophagic protein degradation including p62, which further activated NRF2. In vivo, chronic iAs exposure activated NRF2 in both epithelial and stroma cells of chimeric human prostate grafts and induced premalignant events.Conclusions:Low-dose iAs increased self-renewal and decreased differentiation of human PrSPCs by activating the p62-NRF2 axis, resulting in epithelial cell transformation. NRF2 is activated by iAs through specific autophagic flux blockade in progenitor cells, which may have potential therapeutic implications. https://doi.org/10.1289/EHP6471

Abstract D090: Can exposure to environmental chemical and biologic agents increase the risk of prostate cancer and its outcomes?

Abstract Introduction: It is generally believed that the environment plays some role in the development of prostate cancer, but the extent of that role is not understood. The objective of this study is to perform a systematic review of the literature to bring together the best available evidence on the suspected relationship between the environment and prostate cancer. Methods: PubMed, Web of Science, CINAHL, CancerLit, and the Cochrane Library were searched. We examined peer-reviewed English language studies examining the association between the environment and prostate cancer risk between 1990 and May 31, 2019. We further included studies if they met all of the following criteria: (1) considered at least one chemical or biological agents; (2) reported risk for incidence, mortality, serious adverse events, or hospital admissions. We extracted data from each study, including location, health outcome, and risk estimates. Results of the studies were combined using a qualitative synthesis due to the variation across and within outcomes in reported results. Results: We assessed 198 studies, of which we selected 51 for an in-depth review. Thirty-four articles fulfilled our predetermined inclusion criteria and were included in the qualitative synthesis. Of the 34 articles, 16 were prospective cohort studies, and 9 were case-control studies. These 34 articles explored a number of environmental agents including chemicals, ionizing radiation, electromagnetic fields, and infectious agents. Chemical exposures included second-hand exposure to industrial chemicals and to environmental carcinogens. Several of the studies (n=21) were based on ecological comparisons and did not provide a quantitative risk estimate. Exposure to ionizing radiation and electromagnetic fields showed no association with risk of prostate cancer. There is an inconsequential link between pesticides and an increased risk of prostate cancer through a potential endocrine-disrupting mechanism based on androgen imbalance. In most cases the overall evidence was inadequate in number, reported outcomes, quality of study to establish a relationship between a specific environmental agent and risk of prostate cancer; the evidence from chemical exposure studies was not sufficient to draw an inference. Conclusions: Overall, the reviewed epidemiologic evidence provides a weak level of evidence supporting the hypothesis that there is a causal relationship between environmental exposures and increased risk of prostate cancer. Because a large number of individuals are exposed to suspected environmental carcinogens, investigation of the association between prostate cancer and environmental chemical and biological agents deserves to be a high priority. Such investigations do not only have health implications but can also provide a fundamental understanding of the process of prostate carcinogenesis. Citation Format: Oluwabunmi Dada, Hadiza Galadima, John Cyrus, Georges Adunlin. Can exposure to environmental chemical and biologic agents increase the risk of prostate cancer and its outcomes? [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D090.

Dietary Tomato Varieties Similarly Inhibit Prostate Carcinogenesis in the TRAMP Model in Association with Distinct Transcriptomic and Metabolomic Profiles

Abstract Objectives Lycopene intake is associated with reduced risk of prostate cancer, especially lethal disease. Tangerine tomatoes contain highly bioavailable lycopene isomers, compared to red tomatoes, but impact of isomers on cancer preventive bioactivity are unknown. Our goals are: (1) to determine if feeding tomato containing diets with differing lycopene isomers inhibit transgenic adenocarcinoma of the mouse prostate (TRAMP) carcinogenesis, and (2) to determine key early metabolic and transcriptional pathways through which tomatoes act to prevent carcinogenesis. Methods We examine prostate carcinogenesis in the TRAMP model, comparing two tomatoes with distinct lycopene isomer profiles: all-trans-lycopene-rich red tomatoes and cis-lycopene-isomer-rich tangerine tomatoes. Weanling TRAMP and wild type (WT) mice were fed AIN-93 G control, 10% tangerine tomato + AIN-93 G (w/w), or 10% red tomato + AIN-93 G (w/w) diet until 10 or 18 wks. At 10 wks., prostate RNA-seq and plasma metabolomics were performed on TRAMP and WT samples. At 18 wks., plasma carotenoid analysis and histopathology was performed on TRAMP mice. Results At 18 wks., plasma lycopene concentrations were 2.84-fold greater in tangerine tomato-fed mice than red tomato-fed mice (p &amp;lt; 0.0001), yet both red and tangerine tomato diets similarly prevent carcinoma incidence compared to the control diet by 43% and 36% respectively (p &amp;lt; 0.001, both vs. control). Our investigation of early carcinogenesis (10 wks.) shows that both tomato diets similarly impact the plasma metabolome, and we define prostate transcriptomic profiles mediated by TRAMP genotype, such as inflammation- and immune-regulated pathways, that are inhibited by dietary tomato. We identify an inflammatory gene panel (Olr1, Il1a, Cscl9, and Ccl22) which is inhibited by tomato diets. In a human prostate cancer database, higher expression of this gene panel is associated with a more aggressive phenotype. Conclusions Together, our results implicate red and tangerine tomatoes as potentially beneficial for the inhibition of early prostate carcinogenesis through the modulation of transcriptional programs centered on inflammation and the immune response. Our findings support efforts to test novel tomato products for the inhibition of human prostate carcinogenesis. Funding Sources AICR, NIH P30, USDA NNF.

Impact of Dietary Tomato on Prostate Carcinogenesis and Progression in Lean and Overweight/Obese TRAMP Mice

Abstract Objectives The primary objective was to determine the effect of dietary tomato on prostate cancer (PCa) development and progression in overweight/obese, transgenic mice prone to PCa (TRAMP mice). Secondary objectives included assessing histological, inflammatory, angiogenic, and metabolic changes in prostate tumors at different time points of cancer progression. Methods 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% freeze-dried tomato powder (TP). Prostate tumor incidence and growth were monitored via ultrasound imaging. Mice were terminated one or four weeks following tumor development to assess early and later molecular changes in the tumors. Results OB diets led to greater body weight over time (45.2 ± 1.0 g at 24 weeks of age) when compared with CON diets (33.2 ± 0.8 g; p &amp;lt; 0.0001 by 2-way ANOVA), with TP inclusion having no impact on body weight within diets. OB diets resulted in greater tumor incidence (64.8% vs. 42.5%), earlier age at tumor onset (16.9 ± 1.0 weeks vs. 18.6 ± 0.7 weeks), higher body weight at tumor detection (38.6 ± 1.0 g vs. 30.8 ± 1.2 g), and greater post-mortem periprostatic adipose weight (2.0 ± 0.1 g vs. 0.9 ± 0.1 g). TP intake was protective only in lean animals, with CON-TP-fed animals having exhibited lower tumor volume at detection (28.7 ± 5.2 mm3 vs. 47.3 ± 15.5 mm3) and lower tumor weight at both one (0.1 ± 0.02 g vs. 0.2 ± 0.06 g) and four (1.5 ± 0.3 g vs. 2.1 ± 0.5 g) weeks following tumor detection compared with CON-fed animals. Conversely, TP was not protective in animals with obesity, with OB-TP-fed animals having exhibited no differences in tumor weight one week following tumor detection (0.3 ± 0.06 g vs. 0.3 ± 0.07 g) and greater tumor weight four weeks following tumor detection (2.5 ± 0.7 g vs. 2.0 ± 0.3 g) when compared with OB-fed animals. Conclusions TRAMP mice fed obesogenic diets have higher body weight and earlier onset of PCa. While tomato intake led to smaller tumors in lean animals, the opposite effect was observed in animals with higher body weight. Funding Sources This research is supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health.

Can Tomato Powder Reduce Radiation-Induced Effects in a Murine Model of Prostate Cancer?

Abstract Objectives Tomatoes contain carotenoids and other potent antioxidants that may protect the surrounding tissue from the detrimental effects of external beam radiation therapy, while reducing rates of prostate carcinogenesis. The objective of this study was to determine whether dietary lyophilized tomato paste (TP) alters early inflammatory and oxidative events following a single dose of radiation and leads to a more successful therapeutic outcome. Methods Male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice (n = 76) were provided a powdered AIN-93 G diet (Control) or a modified AIN-93 G diet containing 10% TP (w/w) at 4 weeks of age. Mice were monitored by ultrasound for in vivo tumor detection and 3-D volumetric measurement biweekly. Once tumors reached a volume of 1000 mm3, the caudal half of the mouse was irradiated with 7.5 gy (Rad, n = 18–19 per diet) or 0 gy (sham, n = 16–20 per diet) with a Cobalt-60 source. Mice were euthanized 24 hours after radiation or sham treatment. Antioxidants (carotenoids and α-tocopherol) were measured by high performance liquid chromatography (HPLC) in the serum, tumor, prostate, and liver. Sections of tumor, liver, kidneys, bladder, lymph, bladder and intestines were stained by hematoxylin and eosin (H&amp;E) and cleaved-caspase 3 were assessed for radiation-induced changes and apoptosis. Inflammatory markers (C-reactive protein, IL-6, IL-17A, TNFα, IFNγ, and IL-10) were measured in serum, liver, prostate, tumor, and epididymal adipose tissues by ELISA. Results This study is the first to explore the effects of TP on the tumor microenvironment following irradiation. Initial results suggest that TP consumption does not alter circulating or tissue (liver and prostate) concentrations of inflammatory markers (C-reactive protein, TNFα, IFNγ, IL-6, IL-17, or IL-10). We hypothesize that TP-Rad will maintain similar levels of circulating concentrations of antioxidants (carotenoids and α-tocopherol) compared to sham-treated mice. Additionally, we hypothesize that TP will reduce markers of cell damage in surrounding tissues. Conclusions This study will provide important preclinical data to inform future clinical trials evaluating approaches to lessen extra-prostatic damage from radiation therapy and thus improve therapeutic outcomes. Funding Sources This work was supported by USDA NIFA ILLU-971–334.

Inflammatory and insulinemic dietary patterns: Influence on circulating biomarkers and prostate cancer risk in the prostate, lung, colorectal and ovarian cancer (PLCO) cohort.

e17561 Background: Prostate cancer (PCa) is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. Methods: First, we examined associations of the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores with circulating concentrations of relevant biomarkers, to assess the validity of these two dietary patterns. Secondly, we investigated associations of the EDIH and EDIP with risk of PCa (total, low-grade, high-grade, advanced and lethal). EDIH and EDIP dietary scores calculated from food frequency questionnaire data for 3,517 men and women who provided a blood sample at enrollment, were used to validate dietary patterns against known relevant biomarkers. A separate sample of 49,317 men was used to evaluate the associations of EDIH and EDIP with prostate cancer risk. We used multivariable-adjusted linear regression to compute the percent change and 95% confidence intervals (95%CI) in biomarker concentrations, and Cox regression to estimate hazard ratios (HR) and 95%CI for PCa risk; in dietary score quintiles, using the lowest quintile as reference. Results: Compared to the lowest quintile, participants in the highest EDIH quintile (most hyperinsulinemic diets) had significantly higher concentrations of C-peptide, insulin, CRP, and TNF-R2 and lower adiponectin. Those consuming the most pro-inflammatory diets (EDIP) had significantly higher concentrations of IL-6, TNF-R2, C-peptide and insulin with lower adiponectin. Men classified in EDIH quintile 5 compared to 1, were also at higher total PCa risk: HR, 1.11; 95%CI, 1.01, 1.23; P-trend = 0.03, especially high-grade cancer: HR, 1.18; 95%CI, 1.02, 1.37; P-trend = 0.06; whereas the EDIP was not associated with risk. Conclusions: EDIH and EDIP predicted concentrations of biomarkers relevant to the insulinemic and inflammatory potential of diet in PLCO. EDIH predicted future PCa risk and may suggest a dietary pattern for PCa prevention.