Differential effects of jaboticaba peel extract administration on PCa progression in TRAMP mice depend on the androgenic status of the prostatic milieu and are driven by angiogenesis regulation

Author(s)

Rezende, Bianca B. ; Vecchi, Ana Clara T. ; Marostica Jr, Mario R. ; Cagnon, Valeria H. A. ; Montico, Fabio

• Document type: Journal article
• Source: Food Research International; v. 208, p. 26-pg., 2025-03-18.

Abstract

Jaboticaba peel extract (JPE) has demonstrated chemopreventive effects on the development of prostatic lesions in experimental systems, including the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP). However, its influence over castration-resistant prostate cancer (CRPC) and the androgenic dependence of its actions in this model remain unknown. Therefore, we aimed to evaluate JPE effects on TRAMP mice tumorigenesis under different androgen reliance settings. Mice were submitted to short- or long-term JPE administration, associated or not with androgen deprivation therapy (ADT) by surgical and chemical castration. Prostate, periaortic lymph nodes and lung samples were harvested to determine the incidence of primary and metastatic lesions. Protein expression of proliferative, hormonal and angiogenesis markers was evaluated. Results showed that JPE administration in a hormone naive setting restricted poorly-differentiated tumors to the ventral prostate. Additionally, treatment extension improved the proportion of tumor-free individuals and the timeline for the development of palpable tumors. These results were paralleled by significant increment on VE-Cadherin expression. Furthermore, JPE-treated groups demonstrated significantly lower incidences of lymphatic metastasis. Conversely, JPE plus ADT resulted in poor outcomes, especially upon the extension of this association. In this setting, decreased survival, lower tumor-free mice proportion and increment of proliferative epithelial areas were registered. Altogether, such effects were attributed to a time-dependent up- (VEGF, latent TGF-(32 and TGF(3-RI) or downregulation (VEGFR-2 and VE-Cadherin) of angiogenic mediators expression. Therefore, we conclude that long-term ADT in TRAMP mice drives the prostatic microenvironment dynamics towards a proangiogenic state, which negatively impacts or even abolishes the otherwise beneficial effects of JPE. (AU)

• FAPESP's process: 22/09493-9 - Metabolomic in vitro studies of fruit anthocyanins for understanding its mechanisms of action against Obesity
• Grantee: Juliano Lemos Bicas
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/09692-1 - Brazilian berry (Myrciaria jaboticaba) peel extract as an adjuvant therapy to androgen deprivation in castration-resistant Prostate Cancer: studies on apoptosis and tumor neovascularization regulatory mechanisms
• Grantee: Fabio Montico
• Support Opportunities: Regular Research Grants
• FAPESP's process: 23/17076-1 - Technological, nutritional and functional potential of by-product flours from the production chain of Cambuci (Campomanesia phaea) and passion fruit from Caatinga (Passiflora cincinnata Mast.)
• Grantee: Juliano Lemos Bicas
• Support Opportunities: Regular Research Grants