RESUMEN
Blood vessels and nerves are complex, branched structures that share a high degree of anatomical similarity. Guidance of vessels and nerves has to be exquisitely regulated to ensure proper wiring of both systems. Several regulators of axon guidance have been identified and some of these are also expressed in endothelial cells; however, the extent to which their guidance functions are conserved in the vascular system is still incompletely understood. We show here that the repulsive netrin receptor UNC5B is expressed by endothelial tip cells of the vascular system. Disruption of the Unc5b gene in mice, or of Unc5b or netrin-1a in zebrafish, leads to aberrant extension of endothelial tip cell filopodia, excessive vessel branching and abnormal navigation. Netrin-1 causes endothelial filopodial retraction, but only when UNC5B is present. Thus, UNC5B functions as a repulsive netrin receptor in endothelial cells controlling morphogenesis of the vascular system.
Asunto(s)
Vasos Sanguíneos/embriología , Vasos Sanguíneos/metabolismo , Morfogénesis , Receptores de Superficie Celular/metabolismo , Animales , Vasos Sanguíneos/anomalías , Vasos Sanguíneos/citología , Movimiento Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Ratones , Datos de Secuencia Molecular , Mutación/genética , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Receptores de Netrina , Netrina-1 , Seudópodos/efectos de los fármacos , Seudópodos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/genética , Proteínas Supresoras de Tumor , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez CebraRESUMEN
Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening.