Developmental effects of von Hippel–Lindau gene deficiency

Abstract

The histogenetic origin and the basis of the distribution of central nervous system (CNS) hemangioblastomas in the von Hippel-Lindau (VHL) tumor suppressor gene syndrome, VHL disease, are unknown. To better understand hemangioblastoma histogenesis, we analyzed postmortem CNS tissues from four patients with well-established diagnosis of VHL disease including development of characteristic tumors and positive family history. Numerous angiomesenchymal tumorlets, which resembled hemangioblastoma, but which also consistently showed distinct histological features, were distributed in the nerve roots, spinal cord, and cerebellum. Genetic analysis consistently showed deletion of the wild-type VHL allele in these tumorlets. Most angiomesenchymal tumorlets were in the dorsal nerve roots; the anterior roots and cerebellum were less frequently affected. Tumorlet distribution was highly consistent in the four cases. In analogy to the wide morphological spectrum of lesions known to exist in VHL kidneys, nerve roots appear to harbor more wide-spread and morphologically heterogeneous changes than previously appreciated. The abundance of tumorlets, associated with highly consistent morphology and topography, suggests a developmental origin of hemangioblastoma. Therefore, in VHL disease, inactivation of the VHL wild-type allele appears necessary, but not sufficient, for the formation of tumor that produces symptoms and neurological disability.

Coexpression of erythropoietin and erythropoietin receptor in sporadic clear cell renal cell carcinoma

“…Expression of Epo is secondary to VHL gene deficiency, 15,16 whereas EpoR expression normally occurs in development as part of a response to hypoxia. 11,12 With inactivation of VHL protein in cells, however, Epo and EpoR coexpression persists in tumor precursor cells. 11,12 Retention of Epo and EpoR coexpression may lead to cell proliferation via autocrine stimulation, which appears to be an essential step in renal carcinoma tumorigenesis.…”

“…11,12 With inactivation of VHL protein in cells, however, Epo and EpoR coexpression persists in tumor precursor cells. 11,12 Retention of Epo and EpoR coexpression may lead to cell proliferation via autocrine stimulation, which appears to be an essential step in renal carcinoma tumorigenesis. 24,25 There is evidence that in the kidney nephrogenous mesenchyme has a pluripotent capacity and gives rise to the renal epithelium, mesenchymal as well as stromal elements.…”

“…This in turn mediates the upregulation of HIF protein that induces the activation of downstream pathway including erythropoietin (Epo) and vascular endothelial growth factor (VEGF), thus promoting angiogenesis and other changes in cellular metabolism. [6][7][8][9][10] Recent data in VHL-associated tumors such as hemangioblastomas, 11,12 renal cell carcinomas 13 and endolymphatic sac tumors 14 implicate coexpression of Epo and its receptor (EpoR) in their tumorigenesis. Expression of Epo is thought to be secondary to the VHL gene deficiency, 15,16 whereas EpoR expression occurs in normal development as part of the response to hypoxia.…”

“…Expression of Epo is thought to be secondary to the VHL gene deficiency, 15,16 whereas EpoR expression occurs in normal development as part of the response to hypoxia. 11,12 Clear cell renal cell carcinoma (CCRCC) comprises approximately 80% of all sporadic renal cell carcinomas. [17][18][19] The VHL tumor suppressor gene is the most commonly mutated gene in sporadic CCRCC.…”

Growth Mechanisms of Schwann Cell Tumors in NF2

“…In addition to cerebellar hemangioblastomas affected VHL patients were found to have many angio-mesenchymal tumorlets in the dorsal nerve roots. As in NF2, loss of heterozygosity for the VHL gene was found already in the angio-mesenchymal lesions, suggesting that, (as in NF2) inactivation of the VHL wild type allele is necessary, but not sufficient for the formation of a symptomatic tumor 12 . The hypothesis that there are additional "hits" subsequent to the loss of NF2 allele in schwannomas was proposed by Woods et al 13 but very few schwannomas were found to have genomic alterations (amplifications or deletions) with comparative genomic hybridization 14 .…”