RESUMEN
To elucidate the sequence of molecular events intricate with angiogenesis and the initiation and progression prostate cancer, the temporal and spatial expression patterns of platelet endothelial cell adhesion molecule-1 (PECAM1/CD31), hypoxia-induced factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and the cognate receptors VEGFR1 and VEGFR2 were characterized. Immunohistochemical and in situ analyses of prostate tissue specimens derived from the spontaneous autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model identified a distinct early angiogenic switch consistent with the expression of PECAM-1, HIF-1alpha, and VEGFR1 and the recruitment of new vasculature to lesions representative of high-grade prostatic epithelial neoplasia (PIN). During progression of prostate cancer, the intraductal microvessel density (IMVD) was also observed to increase as a function of tumor grade. Immunoblot and in situ analyses further demonstrated a distinct late angiogenic switch consistent with decreased expression of VEGFR1, increased expression of VEGFR2, and the transition from a differentiated adenocarcinoma to a more poorly differentiated state. Analysis of clinical prostate cancer specimens validated the predictions of the TRAMP model. This resolution of prostate cancer-associated angiogenesis into distinct early and late molecular events establishes the basis for a "progression-switch" model to explain how the targets of antiangiogenic therapy might change as a function of tumor progression.
Asunto(s)
Adenocarcinoma/irrigación sanguínea , Neovascularización Patológica/metabolismo , Neoplasias de la Próstata/irrigación sanguínea , Factores de Transcripción , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Diferenciación Celular/fisiología , Proteínas de Unión al ADN/biosíntesis , Progresión de la Enfermedad , Factores de Crecimiento Endotelial/biosíntesis , Factores de Crecimiento Endotelial/sangre , Humanos , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Linfocinas/biosíntesis , Linfocinas/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Patológica/patología , Proteínas Nucleares/biosíntesis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/biosíntesis , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Isoformas de Proteínas , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento Endotelial Vascular , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Prostate cancer continues to be the second leading cancer related death among men. In order to more fully develop effective prevention and intervention strategies for this prevalent disease, the underlying molecular mechanisms of initiation, progression and metastatic spread must be understood. To this end mouse models have an essential role in prostate cancer research in that they can closely mimic the pathological and biochemical features of the disease. In this review we discuss the history of autochthonous murine models of prostate cancer, the essentials of the idealized mouse model for prostate cancer and speculate on approaches towards this goal.