RESUMEN
Cancers are believed to arise from cancer stem cells (CSCs), but it is not known if these cells remain dependent upon the niche microenvironments that regulate normal stem cells. We show that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state. Increasing the number of endothelial cells or blood vessels in orthotopic brain tumor xenografts expanded the fraction of self-renewing cells and accelerated the initiation and growth of tumors. Conversely, depletion of blood vessels from xenografts ablated self-renewing cells from tumors and arrested tumor growth. We propose that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.
Asunto(s)
Neoplasias Encefálicas/irrigación sanguínea , Células Endoteliales , Células Madre Neoplásicas , Antígeno AC133 , Animales , Antígenos CD/metabolismo , Neoplasias Encefálicas/metabolismo , Comunicación Celular/fisiología , Células Cultivadas , Técnicas de Cocultivo , Células Endoteliales/metabolismo , Femenino , Expresión Génica , Glicoproteínas/metabolismo , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Hibridación Fluorescente in Situ , Ratones , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Neuronas/metabolismo , Neuronas/patología , Péptidos/metabolismoRESUMEN
BACKGROUND: We evaluated the potential of bioluminescence imaging (BLI) for early tumor detection, demonstrating occult sites of disseminated disease and assessing disease progression in a murine model of neuroblastoma. METHODS: Neuroblastoma cells engineered to express the enzyme firefly luciferase were used to establish localized tumors and disseminated disease in SCID mice. Bioluminescent signal intensity was measured at serial time points, and compared with traditional methods of evaluating tumor growth. RESULTS: Bioluminescence imaging detected subcutaneous and retroperitoneal tumors weeks before they were palpable or appreciable by ultrasound. Bioluminescent signal intensity at both sites then paralleled tumor growth. After intravenous administration of tumor cells, BLI revealed disseminated disease in the liver, lungs, and bone marrow, again weeks before any gross disease was present. The presence of tumor within these sites at early time points was confirmed by reverse transcriptase-polymerase chain reaction. Finally, BLI permitted a real-time, noninvasive, quantitative method for following response to therapy in a model of minimal residual disease. CONCLUSION: Bioluminescence imaging detects tumor much earlier than traditional methods. In addition, it can detect, quantify, and follow micrometastasis in real-time during disease progression. This methodology is extremely valuable for studying tumor tissue tropism, mechanisms of metastasis, and response to therapy in murine tumor models.