Finasteride effects on epithelium-stroma interaction in the different rat prostatic lobes / Efeito da finasterida sobre a interação epitelio-estroma nos diferentes lobos da prostata de rato

AUTOR(ES)
DATA DE PUBLICAÇÃO

2006

RESUMO

Prostate cancer cells are generally dependent on androgen stimulation mediated by the androgen receptor (AR) for growth and survival. Therefore, hormonal manipulation, such as castration and/or the use of AR antagonists, results in a regression of the cancer. However, these treatments very rarely lead to the cure of advanced disease and cancer eventually become androgen-independent. A substantial amount of evidence supports the hypothesis that Matrix Metalloproteinases (MMPs) play a key role in multiple steps of tumor progression, including tumor promotion, angiogenesis, invasion, and metastasis. MMPs constitute a broad family of zinc-binding endopeptidases that play a key role in degradation of the extracellular matrix and basement membrane. Two important members of the MMP family, MMP-2 and MMP-9, belonging to the gelatinase subfamily, are known to specifically cleave type IV collagen, the major component of basement membranes. Recently, The Prostate Cancer Prevention Trial (PCPT) showed that finasteride, a 5 alphareductase inhibitor widely employed in the treatment of benign prostatic hyperplasia, significantly decreased the incidence of prostate cancer versus placebo. However, Gleason score 7-10 tumors were significantly more common in the finasteride versus the placebo group. In this sense, the role of finasteride for prostate cancer chemoprevention needs further examination. Thus, this study examined whether the finasteride-induced changes on prostate morphology and phisiology has an impact on MMP-2 and MMP-9 expression and activity. Male Wistar rats (90 days of age) were treated daily with finasteride subcutaneously injected (25mg/Kg) during 3, 7, 30 and 90 days. A control group of animals received daily doses of vehicle (corn oil). The ventral (VPs), dorsolaterals (DLPs) and anterior (APs) lobes had been dissected, weighed and processed for citochemistry, immunocitochemistry, morphometric-stereological, and zymography analyses. Finasteride promoted a progressive involution in the epithelium and lumen compartments, reduced of the epithelial cell heights and proliferation and increased apoptosis and the stromal area in the three prostatic lobes. Gelatin zymography analysis showed that finasteride treatment changed the gelatinolitic profile in the prostatic lobes, with an increase in the pro-MMP-9 at day 30 and in the active-MMP-9 at days 30 and 90 in VP, increase in the pro-MMP-9 inDLP at days 7 and 30 and an increase in the intermediate-MMP-2 in PA at day 7. However, finasteride induced-atrophy did not cause a significant increase in MMPs activity, in contrast with is found in androgen ablation by castration. This is probably due to the fact that finasteride changes in prostate are a slow process in comparison with castration. Take together, our results suggest that finasteride is effective in treating prostate diseases without creating a most favorable environment for tumor growth invasion and metastasis.

ASSUNTO(S)

apoptosis metaloproteinas prostate extracellular matrix apoptose matriz extracelular prostata metalloproteins zymography zimografia

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