RESUMEN
The urothelium is constantly rebuilt by normal urothelial cells to regenerate damaged tissues caused by stimuli in urine. However, the urothelial carcinoma cells expand the territory by aberrant growth of tumor cells, which migrate and occupy the damaged tissues to spread outside and disrupt the normal cells and organized tissues and form a tumor. Therefore, the interaction between normal urothelial cells and urothelial carcinoma cells affect the initiation and progression of urothelial tumors if normal urothelial cells fail to migrate and adhere to the damages sites to regenerate the tissues. Here, comparing normal murine urothelial cells with murine urothelial carcinoma cells (MBT-2), we found that normal cells had less migration ability than carcinoma cells. And in our co-culture system we found that carcinoma cells had propensity migrating toward normal urothelial cells and carcinoma cells had more advantages to adhere than normal cells. To reverse this condition, we used anabolic androgen, dihyrotestosterone (DHT) to treat normal cells and found that DHT treatment increased the migration ability of normal urothelial cells toward carcinoma cells and the adhesion capacity in competition with carcinoma cells. This study provides the base of a novel therapeutic approach by using anabolic hormone-enforced normal urothelial cells to regenerate the damage urothelium and defend against the occupancy of carcinoma cells to thwart cancer development and recurrence.
Asunto(s)
Andrógenos/farmacología , Comunicación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Dihidrotestosterona/farmacología , Células Epiteliales/efectos de los fármacos , Urotelio/efectos de los fármacos , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Cocultivo , Cámaras de Difusión de Cultivos , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Expresión Génica , Genes Reporteros , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Masculino , Ratones , Cultivo Primario de Células , Urotelio/citología , Urotelio/metabolismoRESUMEN
Dysregulated androgen receptor (AR) signaling is implicated in several types of tumor, including carcinomas of the prostate, breast, liver and bladder. However, the contribution of AR to the progression of upper urinary tract urothelial carcinomas (UUTUC) has not been fully investigated. In the present study, we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells. We investigated the role of the AR in UUTUC by using UUTUC-derived BFTC 909 cells. The overexpression of AR promotes the migration and invasion of BFTC 909 cells. Expression of migration/invasion-related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses. The results showed that AR-enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix-degrading enzyme MMP-9 and cyclooxygenase (COX)-2. Subsequently, the blocking of MMP-9 and COX-2 signaling by inhibitors suppressed AR-enhanced cell migration and invasion. The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT. Thus, the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer.
Asunto(s)
Movimiento Celular/genética , Ciclooxigenasa 2/genética , Metaloproteinasa 9 de la Matriz/genética , Receptores Androgénicos/genética , Neoplasias Urológicas/patología , Línea Celular Tumoral , Ciclooxigenasa 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Receptores Androgénicos/metabolismo , Regulación hacia Arriba , Sistema Urinario/enzimología , Sistema Urinario/metabolismo , Sistema Urinario/patología , Neoplasias Urológicas/enzimología , Neoplasias Urológicas/genética , Neoplasias Urológicas/metabolismo , Urotelio/metabolismo , Urotelio/patologíaRESUMEN
Androgen receptor (AR) plays a critical role in bladder cancer (BCa) development. Our early studies found AR knock-out mice (with few androgens and deleted AR) failed to develop BCa, yet 50% of castrated mice (with few androgens and existing AR) still developed BCa in an N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) carcinogen-induced BCa mouse model, suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens. The mechanism underlying this and/or which factors potentiate AR function at the castration level of androgen remains unclear. Epidermal growth factor (EGF), a key player in BCa progression, has been demonstrated to be able to potentiate AR transactivation in prostate cancer. In the present study, we found that EGF could increase BCa cell growth, migration and invasion in the presence of AR under the low amount of androgen and EGF was able to potentiate AR transactivation through EGFR by activating PI3K/AKT and MAPK pathway at castration androgen level. The increased suppression effects by EGFR inhibitor of PD168393 on AR function after addition of anti-androgen, Casodex, further suggested AR might play a key role in the effects of EGF on BCa progression and metastasis. Collectively, our results indicate that EGF may be able to potentiate AR transactivation that leads to enhancing BCa progression, which may help us to develop a better therapeutic approach to treat BCa via targeting both EGF and AR signaling.