Dietary Tomato Reduces Castration‐Resistant Prostate Cancer Burden in the TRAMP Model

Abstract

Epidemiological evidence continues to support the hypothesis that consumption of diets rich in tomato products are associated with a reduced risk of prostate cancer, a relationship supported by studies in rodent models. Castration‐resistant prostate cancer (CRPC) represents the late and lethal phase of human prostate carcinogenesis, and is defined as cancer progression after surgical castration or pharmacologic reduction of serum testosterone through androgen deprivation therapy (ADT). One mechanism involved in the transition to CRPC is cancer cells’ acquired capacity for androgen synthesis. We have previously shown that dietary tomato can reduce prostatic expression of androgen biosynthetic genes. Therefore, we questioned whether dietary tomato might be effective in preventing or controlling the progression of CRPC. We hypothesized that lifelong dietary intake of tomato, as well as dietary tomato intervention following castration, would reduce tumor burden and growth rate in a mouse model of CRPC. TRAMP mice (3 weeks of age, n=79) were acclimated to a powdered, AIN‐93G diet (CON) for one week and then randomized to consume CON (n=28) or 10% w/w lyophilized tomato paste (TP; n=27) from 4 weeks of age until euthanization. A third group, modeling adjuvant dietary intervention, consumed CON from 4 weeks of age until 12 weeks of age, and then 10% w/w lyophilized tomato paste from week 12 until euthanization (TP‐I; n=25). All animals were castrated at 12 weeks of age. Beginning at 10 weeks of age, mice were monitored longitudinally with biweekly ultrasound scans for tumor detection. For each ultrasound scan, serial 2D image slices were used to generate a 3D volume measurement. Upon tumor detection, mice were switched from biweekly to weekly scans and imaged 4 additional times for volumetric tumor measurement and determination of tumor growth rate. Two criteria were implemented for euthanasia: after 5 tumor scans (detection + 4 weekly), or if no tumor had been detected by 30 weeks of age. Longitudinal tumor area under the curve (AUC), as measured by ultrasound, was reduced nearly 50% by tomato intervention (TP‐I) and approximately 25% by lifelong tomato consumption (TP). At euthanization, TP‐I, but not TP, reduced tumor weight approximately 30%. Both measures of tumor burden (tumor growth AUC and tumor weight at euthanization) were reduced by the adjuvant TP‐I, while only tumor growth AUC was decreased by lifelong TP. Observational studies have shown that the lycopene content of the tomato diets in the present study, in human equivalent dose, is both achievable and protective against prostate cancer. Previously, we have shown that lifelong tomato consumption reduces cancer incidence in TRAMP models of primary prostate cancer; current results suggest that pathways regulating primary and castration‐resistant prostatic carcinogenesis in the TRAMP model may be differentially impacted by lifelong tomato feeding. Future work should address efficacy of adjuvant dietary tomato with pharmacologic ADT to assess the potential for this approach to translate into clinical benefits for men with CRPC.Support or Funding InformationThis work is supported by the USDA NIFA Hatch project ILLU‐971‐334 and NIH R37 EB002641.