Reactive stroma and prostate: senescence and angiogenesis inhibition x glandular lesions in the TRAMP model

Author(s)

Fabio Montico

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2014-06-06

Examining board members

Valéria Helena Alves Cagnon; Irene Bastos Franceschini Vicentini; Cleida Aparecida de Oliveira; Maira Aparecida Stefanini; Sebastião Roberto Taboga

• Advisor: Valéria Helena Alves Cagnon

Abstract

Senescence is associated with hormonal changes in the prostate, leading to a permissive microenvironment for the development of neoplastic lesions. Prostatic angiogenesis is an androgen-regulated process which is fundamental for tumor growth and represents an important event in cancer-associated reactive stroma. Thus, angiogenesis inhibition emerges as a promising therapy in the treatment of prostate neoplasms. The aim herewith was to characterize prostatic stroma during senescence and following antiangiogenic and hormonal ablation therapies, comparing the findings with the reactive stroma phenotype associated to TRAMP model glandular lesions. Elderly male FVB mice (52 week-old) were submitted to antiangiogenic treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Hormonal blockage was achieved with finasteride administration (20mg/kg; s.c.), either alone or combined to both inhibitors. After 21 days of treatment, dorsolateral prostate samples were collected for morphological, immunohistochemical and Western Blotting analysis. Senescence led to the occurrence of inflammatory foci and proliferative lesions in the prostate, apart from increased frequency of CD34/VIM and CD34/?SMA positive cells and raised levels of MMP-9, IGFR-1, VEGF, HIF-1?, FGF-2, CD31, VIM and ?SMA, resembling TRAMP mice prostatic microenvironment. On the other hand, endostatin and TGF-? showed higher expression in senescence but not during tumor progression in the TRAMP model. Antiangiogenic treatment resulted in recovery and/or interruption of the senescence-associated glandular changes, showing differential effects for each drug. SU5416 acted mainly on prostatic tissue remodeling, reducing MMP-9, VIM and ?SMA levels as well as the frequency of CD34/VIM and CD34/?SMA positive cells, whereas TNP-470 influenced specially IGFR-1, VEGF and HIF-1?, promoting greater inhibition over these factors. The association between the inhibitors led to synergistic differential effects. Despite presenting a trend to regulate positively pro-angiogenic factor expression, finasteride resulted in decreased MMP-9, IGFR-1, VEGF, HIF-1? and FGF-2 levels relatively to controls, either in isolation or combined to antiangiogenic agents. However, unlike angiogenesis inhibition, hormonal ablation did not lead to decreased TGF-? expression. Thus, it was concluded that senescence created a reactive stroma microenvironment which resembles that verified in the TRAMP model and is characterized by stimulated cell proliferation, tissue remodeling, angiogenesis and endothelial-to-mesenchymal transition. This scenario certainly provided favorable conditions for the development of pre-malignant and malignant prostatic lesions. However, the absence of poor-differentiated adenocarcinoma and the lesser distribution of neoplastic lesions in relation to TRAMP mice suggested a possible protective role of endostatin on the prostate during aging. Antiangiogenic therapy was efficient in promoting antitumor effects and neovascularization inhibition, especially following the combination of inhibitors, suggesting that the differential action of these agents on tumorigenic processes results in a broader spectrum of effects for the treatment. Finally, it is noteworthy that beneficial effects from finasteride treatment must be looked carefully, considering the capacity of this drug to promote a reactive stroma microenvironment favorable to the development of glandular disorders (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 Opportunities: Scholarships in Brazil - Doctorate