RESUMEN
Hemangioblastomas are central nervous system (CNS) tumors of unknown histogenesis, which can occur sporadically or in von Hippel-Lindau disease. Hemangioblastomas are composed of neoplastic "stromal" cells of unknown origin, accompanied by intensive reactive angiogenesis. Failure to specify the cytologic origin of the stromal cell has precluded the development of nonsurgical therapies and limits understanding of its basic biology. We report that the stromal cells express proteins (Scl, brachyury, Csf-1R, Gata-1, Flk-1, and Tie-2) that characterize embryonic progenitor cells with hemangioblastic differentiation potential and conclude that embryonic progenitors with hemangioblast potential represent a possible cytologic equivalent of the stromal cell. We also identified a new autocrine/paracrine stimulatory loop between the receptor Tie-2 and the hypoxia-inducible factor target Ang-1, which, combined with previous observations, suggests that a variety of autocrine loops may be initiated in hemangioblastomas, depending on the differentiation status of the tumor cells and the extent of HIF downstream activation. Finally, the consistent identification of Scl in the stromal cells may help explain the unique and characteristic topographical distribution of hemangioblastomas within the CNS.
Asunto(s)
Neoplasias Cerebelosas/metabolismo , Hemangioblastoma/metabolismo , Células Madre Hematopoyéticas/metabolismo , Angiopoyetina 1/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Neoplasias Cerebelosas/enzimología , Neoplasias Cerebelosas/patología , Proteínas Fetales/biosíntesis , Factor de Transcripción GATA1/biosíntesis , Hemangioblastoma/enzimología , Hemangioblastoma/patología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/enzimología , Humanos , Inmunohistoquímica , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas/biosíntesis , Receptor de Factor Estimulante de Colonias de Macrófagos/biosíntesis , Receptor TIE-2/biosíntesis , Células del Estroma/metabolismo , Proteínas de Dominio T Box/biosíntesis , Proteína 1 de la Leucemia Linfocítica T Aguda , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
OBJECTIVE: Hemangioblastomas are benign CNS tumors that occur sporadically or in patients with von Hippel-Lindau (VHL) disease. These tumors are characteristically associated with formation of intra- or peritumoral cysts. Hemangioblastoma cyst formation is a major cause of morbidity and mortality with these tumors. While peritumoral cysts have been suggested to result from vascular leakage, the mechanism of intratumoral cyst formation is not understood. METHODS: To elucidate the origin of intratumoral hemangioblastoma cyst fluid, we characterized its biochemical composition by two-dimensional (2D) proteomic profiling followed by sequencing of several proteins. The proteomic pattern of intratumoral cyst fluid was furthermore compared to the proteomic pattern of serum, hemangioblastoma tumor tissue, and hemangioblastoma peritumoral cyst fluid. RESULTS: We show that proteomic patterns of intra- and peritumoral cyst fluid are identical Both are highly similar to serum and not to tumor. CONCLUSIONS: Intratumoral hemangioblastoma cyst fluid originates from serum. Cyst formation associated with hemangioblastoma, whether peri- or intratumoral, is a consequence of vascular leakage. Anti-VEGF therapy may effectively control hemangioblastoma cyst formation.
