PATHOLOGY, GENETICS AND CELL BIOLOGY OF HEMANGIOBLASTOMAS

Hemangioblastomas are highly vascularized tumors of not well-defined h istological origin which are frequently associated with cysts. They ar ise preferentially in cerebellum, medulla and spinal cord and are hist ologically indistinguishable from vascular lesions in the retina (so-c alled angiomatosis retinae). Hemangioblastomas are the most frequent m anifestations of the von Hippel-Lindau (VHL) disease, an autosomal-dom inant inherited cancer syndrome but also occur as sporadic non-heredit ary tumors. The VHL tumor suppressor gene has recently been cloned and enormous progress has been made towards the understanding of molecula r biology and biological function of the VHL gene. Germline mutations in VHL patients, as well as somatic mutations in different tumors, inc luding hemangioblastomas, have been identified, its ability to act as a tumor suppressor in vivo has been confirmed, and interaction with tr anscription factors Elongin B and C leading to inhibition of transcrip tional elongation has been demonstrated. The mechanism underlying neov ascularization and cyst formation in hemangioblastomas and how this is linked to inactivation of the VHL tumor suppressor gene is not known. However, the finding of dramatic up-regulation of vascular endothelia l growth factor (VEGF), a potent endothelial cell growth factor with v ascular permeability-inducing activity, in stromal cells and the corre sponding receptors, VEGFR-1 and VEGFR-2, in tumor endothelial cells su ggests that angiogenesis and cyst formation in hemangioblastomas may b e regulated by this signaling pathway via a paracrine mechanism.