RESUMEN
The insulin-like growth factor (IGF) axis is a molecular pathway intensively investigated in cancer research. Clinical trials targeting the IGF1 receptor (IGF1R) in different tumors, including prostate cancer, are under way. Although studies on the IGF axis in prostate cancer have already entered into clinical trials, the expression and functional role of the IGF axis in benign prostate and in prostate cancer needs to be better defined. We determined mRNA expression levels of the IGF axis in microdissected tissue specimens of local prostate cancer using quantitative PCR. All members of the IGF axis, including IGF1, IGF2, IGF binding proteins 1 through 6, and insulin receptor, were measured in both the stromal and epithelial compartments of the prostate. IGF1, IGF2, IGF1R, and insulin receptor were down-regulated in local prostate cancer tissue compared with matched benign tissue, suggesting that the IGF axis is not induced during prostate cancer development. Using a new prostate epithelial differentiation model, we demonstrate that the expression of the IGF axis is enhanced during normal prostate epithelial differentiation and regulated by tumor growth factor (TGF)-ß. Our data reveal a functional role of the IGF axis in prostate differentiation, underscoring the importance of the IGF axis in normal development and emphasizing the importance of accurate target validation before moving to advanced clinical trials.
Asunto(s)
Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores de Somatomedina/metabolismo , Somatomedinas/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Diferenciación Celular , Células Cultivadas , Regulación hacia Abajo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Humanos , Técnicas Inmunológicas , Masculino , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the fetal development of the internal urethral sphincter and the gender-related morphologic differences of the bladder outlet. MATERIALS AND METHODS: Thirty-seven (14 female, 23 male) fetal bladder neck specimens (mean gestational age, 19.4 weeks) with the smooth muscle complex of the internal sphincter were investigated histologically. After immunostaining serial sections in 3 reference planes (sagittal, frontal, and horizontal) of the bladder neck, the internal sphincter volumes and bladder outlet diameters were measured and correlated with gender and age of gestation. RESULTS: Between the 18th and 40th week of gestation, an exponential growth of the internal sphincter muscle with significant higher volumes could be observed in male fetuses compared with female fetuses (internal sphincter volumes, P = .006; radius of the sphincter complex, P = .001). As a result of this gender difference, the bladder outlet was significantly (P = .001) narrower in male than in female fetuses. Moreover, we found a significant positive correlation between age and all measured parameters in both male and female specimens. CONCLUSION: The present study indicates a significant closer bladder outlet in male fetuses compared than in females. It thereby provides evidence of a gender-related functional obstruction in addition to a suppositious transient infravesical obstruction in male human fetuses.