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 < 0.0001), yet both red and tangerine tomato diets similarly prevent carcinoma incidence compared to the control diet by 43% and 36% respectively (p < 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.

Transcriptomics and Metabolomics Reveal Tomato Consumption Alters Hepatic Xenobiotic Metabolism and Induces Steroidal Alkaloid Metabolite Accumulation in Mice

“…This article is a US Government work. It is not subject to copyright under 17 The findings and conclusions in this publication are those of the authors and should not be construed to represent any official USDA or U.S. Government determination or policy.…”

“…Prior investigations into the effects of tomato consumption on health have relied on targeted gene expression and phytochemical analyses (e.g. carotenoids) [16][17][18] . While prior investigations have tested singular tomato varieties, it is noteworthy that tomato composition can vary drastically based on genotype and pre/post-harvest environmental conditions [19] .…”

“…The copyright holder for this preprint (which this version posted April 18, 2023. ; https://doi.org/10.1101/2023.04.18.536606 doi: bioRxiv preprint unique to a given cultivar, or a macronutrient matched, tomato-free control diet. Untargeted metabolomic analyses were focused on the more chemically diverse polar/semi-polar compounds since previous studies have investigated differences due to more non-polar carotenoid profiles [16][17][18] .…”

Transcriptomics and Metabolomics Reveal Tomato Consumption Alters Hepatic Xenobiotic Metabolism and Induces Steroidal Alkaloid Metabolite Accumulation in Mice

“…[8][9][10][11]15] Prior investigations into the effects of tomato consumption on health have relied on targeted gene expression and phytochemical analyses (e.g., carotenoids). [9,[16][17][18] While prior investigations have tested singular tomato varieties, it is noteworthy that tomato composition can vary drastically based on genotype and pre/post-harvest environmental conditions. [19] Biological responses to one tomato containing intervention may not be reflective of responses to tomato in general.…”

“…Untargeted metabolomic analyses were focused on the more chemically diverse polar/semi-polar compounds since previous studies have investigated differences due to more non-polar carotenoid profiles. [16,17,20]…”