Antiangiogenic therapy effects on age-associated matrix metalloproteinase-9 (MMP-9) and insulin-like growth factor receptor-1 (IGFR-1) responses: a comparative study of prostate disorders in aged and TRAMP mice

Author(s)

Montico, Fabio ^[1] ; Kido, Larissa Akemi ^[1] ; Hetzl, Amanda Cia ^[1] ; Lorencini, Raisa Mistieri ^[1] ; Candido, Eduardo Marcelo ^[1] ; Alves Cagnon, Valeria Helena ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, BR-13083865 Sao Paulo - Brazil

• Document type: Journal article
• Source: Histochemistry and Cell Biology; v. 142, n. 3, p. 269-284, SEP 2014.
• Web of Science Citations: 9

Abstract

Senescence is associated with hormonal imbalance and prostatic disorders. Angiogenesis is fundamental for the progression of malignant lesions and is a promising target for prostate cancer treatment. The aim was to characterize matrix metalloproteinase-9 (MMP-9) and insulin-like growth factor receptor-1 (IGFR-1) responses in the prostate during senescence and following antiangiogenic and/or androgen ablation therapies, comparing them to cancer progression features in TRAMP mice. Aged male mice (52-week-old FVB) were submitted to antiangiogenic treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c). Finasteride (20 mg/kg; s.c.) was administered alone or associated to both inhibitors. Dorsolateral prostate was collected for light microscopy, and immunohistochemistry and Western blotting collected for MMP-9 and IGFR-1. Senescence led to inflammation and different proliferative lesions in the prostate, as well as to increased MMP-9 and IGFR-1, resembling TRAMP mice prostatic microenvironment. Antiangiogenic therapies promoted recovery and/or interruption of age-associated alterations, presenting differential effects on the molecules studied. SU5416 acted mainly on MMP-9, whereas TNP-470 showed its best influence on IGFR-1 levels. Finasteride administration, alone or in combination with antiangiogenic agents, also resulted in regression of inflammation and neoplastic lesions, besides having a negative modulatory effect on both MMP-9 and IGFR-1. We concluded that stimulated tissue remodeling and proliferative processes during senescence predisposed the prostate to malignant disorders. The combination of different agents was more effective to minimize prostatic imbalance during this period, probably due to the differential action of each drug on factors involved in cell proliferation and extracellular matrix remodeling, resulting in a broader spectrum of effects following the combined treatment. (AU)

• 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 Opportunities: Regular Research Grants
• 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