Tumor derived vasculogenesis in von Hippel-Lindau disease-associated tumors

Abstract

von Hippel-Lindau disease (VHL) patients develop highly vascular tumors, including central nervous system hemangioblastomas. It has been hypothesized that the vascular nature of these tumors is the product of reactive angiogenesis. However, recent data indicate that VHL-associated hemangioblastoma neoplastic cells originate from embryologically-arrested hemangioblasts capable of blood and endothelial cell differentiation. To determine the origin of tumor vasculature in VHL-associated hemangioblastomas, we analyzed the vascular elements in tumors from VHL patients. We demonstrate that isolated vascular structures and blood vessels within VHL-associated hemangioblastomas are a result of tumor-derived vasculogenesis. Further, similar to hemangioblastomas, we demonstrate that other VHL-associated lesions possess vascular tissue of tumor origin and that tumor-derived endothelial cells emerge within implanted VHL deficient UMRC6 RCC murine xenografts. These findings further establish the embryologic, developmentally arrested, hemangioblast as the tumor cell of origin for VHL-associated hemangioblastomas and indicate that it is also the progenitor cell for other VHL-associated tumors.

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

“…2 Several studies have indicated that VHL deficient hemangioblastoma precursor cells, tumorlets, are established during embryonic development, although the exact tumorigenesis is still unknown. [17][18][19][20][21][22] Thus, from birth, vHL patients may harbor numerous microscopic tumorlets in the CNS, including the retina, and similar growth patterns would be expected. Differing anatomical and diagnostic limitations may account for some of the observed disparity in tumor development at the two sites.…”

Von Hippel-Lindau disease involving pancreas and biliary system

“…In cases of VHL disease where the VHL gene is mutated, VHL protein does not bind to HIF1α and activates the expression of a number of factors, including vascular endothelial growth factor, platelet-derived growth factor, erythropoietin, and transforming growth factor, which lead to angiogenesis and tumorigenesis. [5,6] …”

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

“…demands and minimal to no energy reserves, which exacerbate genetic defects in mechanisms regulating metabolism and oxygen sensing (114). While VHL-mediated kidney cancer involves vascular remodeling via angiogenesis, hemangioblastoma formation in neurological tissues of VHL patients may also involve vasculogenic processes (113,115,116). The precise cellular contribution of vascular cells versus tumor "stromal" cells to the dense vascularity of hemangioblastomas remains an open question (113); it is clear, however, that excessive proangiogenic factors such as VEGF-A, PDGF-BB, and EGF drive lesion growth (117,118).…”