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VHL germline mutation (VHL disease) causes tumors within and outside of the central nervous system (CNS). CNS tumorigenesis was recently found to be initiated by multifocal events of maldevelopment. We tested this principle in a frequently affected area outside the CNS, the human epididymis. In this study the earliest sites of epididymal tumorigenesis were analyzed to gain further insight into mesonephric tumorigenesis in patients with VHL disease. Four epididymides were serially sectioned from VHL patients and analyzed by tissue microdissection and LOH analysis, immunohistochemistry for HIF and other VHL protein targets and in-situ hybridization for VHL target protein VEGF. In tumor-free epididymis structural analysis revealed foci of maldeveloped mesonephric material frequently associated with cyst formation. Maldeveloped mesonephric material and cystic structures were VHL-deficient and exhibited activation of HIF-1 and HIF-2 along with the downstream HIF targets VEGF, GLUT-1 and CAIX. Some VHL-deficient cells appeared to be integrated within mature ductules and developed into micropapillary proliferations. In some cases, three-dimensional reconstruction showed micropapillary proliferations to extend deep into the ductular system suggesting neoplastic potential. We conclude -in analogy to human nervous system- that VHL germline mutation (VHL disease) causes primarily developmental changes in epididymal tissue. Microscopic foci of developmental arrest have the potential to develop into tumor and the failure of HIF deactivation may be directly associated with this developmental arrest.

Last updated November 16, 2007