RESUMO
BACKGROUND: Androgen deprivation (AD) as the first-line treatment for advanced prostate cancer (PCa) is insufficient for a long-term effect. Castration resistance remains the greatest obstacle in PCa clinical therapy. Mesenchymal stem cells (MSCs) can migrate into PCa tissues contributing to tumor progression, therefore, in this study we explored the effect of AD on MSC migration to PCa and elicited its importance for the emergence of castration resistance. METHODS: MSC migration assay was performed in several PCa cells (LNCaP, VCaP, and 22Rv1) using in-vivo and in-vitro approaches. Reactive oxygen species generation was evaluated by fluorescence assay. IL-1ß was analyzed by immunohistochemistry, and neutralization experiments were conducted using neutralization antibody. Stem markers (CD133, CD44, and SOX2) were quantified by real-time PCR analysis. The concentration of chemokine ligand 5 was measured by enzyme-linked immunosorbent assay and small hairpin RNA was used for functional analyses. RESULTS: AD could significantly contribute to PCa recruitment of MSCs in vivo and in vitro. AD-induced oxidative stress could promote the inflammatory response mediated by IL-1ß secretion via activating the NF-κB signaling pathway. Moreover, N-acetylcysteine could significantly inhibit MSC recruitment to PCa sites when AD is performed. Furthermore, we found MSCs could increase stemness of PCa cells via promoting chemokine ligand 5 secretion in the AD condition, and consequently accelerate emergence of castration resistance. CONCLUSIONS: Our results suggest that castration in clinical PCa therapy may elicit oxidative stress in tumor sites, resulting in increased MSC migration and in tumor cell growth in an androgen-independent manner. Blocking MSC migration to the tumor may provide a new potential target to suppress castration-resistant PCa emergence.
Assuntos
Androgênios/metabolismo , Inflamação/metabolismo , Células-Tronco Mesenquimais/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Castração/efeitos adversos , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-1beta/genética , Masculino , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/genética , Próstata/metabolismo , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/genéticaRESUMO
Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa cells into androgen-independent manner in vivo and in vitro. Then we found a substantial expression of TGF-ß in MSCs. TGF-ß blockade could significantly inhibit the promotive function of MSCs in PCa cells. Besides that, we also demonstrated androgen might inhibit the expression of TGF-ß in MSCs. Furthermore, we found that either overexpression of SSEA-4 or the number of SSEA-4 positive MSCs in PCa tissues was associated with a shorter cancer-free survival interval (CFSI) and a worse overall survival (OS). Our results suggest that androgen blockade treatment in clinical PCa therapy may elicit the expression of TGF-ß in MSCs, which will result in the transformation of androgen-dependent human PCa cells into androgen-independent manner.