Prostatic Angiogenic Responses in Late Life: Antiangiogenic Therapy Influences and Relation With the Glandular Microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Model

Author(s)

Montico, Fabio ^[1] ; Kido, Larissa Akemi ^[1] ; Hetzl, Amanda Cia ^[1] ; Alves Cagnon, Valeria Helena ^[1]

Affiliation

^[1] Univ Campinas Unicamp, Inst Biol, Dept Struct & Funct Biol, Sao Paulo - Brazil

• Document type: Journal article
• Source: PROSTATE; v. 75, n. 5, p. 484-499, APR 1 2015.
• Web of Science Citations: 10

Abstract

BACKGROUNDAging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. METHODSMale mice (52 week-old FVB) were submitted to treatments with SU5416 (6mg/kg; i.p.) and/or TNP-470 (15mg/kg;s.c.). Finasteride was administered (20mg/kg;s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. RESULTSSenescence led to increased MVD and VEGF, HIF-1 and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1 levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. CONCLUSIONSProstatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy. Prostate 75: 484-499, 2015. (c) 2014 Wiley Periodicals, Inc. (AU)

• FAPESP's process: 11/01968-3 - Reactive stroma and prostate: senescence and angiogenesis inhibition x glandular lesions in the TRAMP model
• Grantee: Fabio Montico
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/03010-4 - Molecular characterization of the prostate after hormonal and antiangiogenic therapies in senile mice (FVB) and in transgenic adenocarcinoma of mice prostate (Tramp) model
• Grantee: Valéria Helena Alves Cagnon Quitete
• Support type: Regular Research Grants