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

2014-02-17 14:13:09

Scientific Reports; 2014 February 17; DOI:10.1038/srep04102

Zhengping Zhuang, Jason M. Frerich, Kristin Huntoon, Chunzhang Yang, Marsha J. Merrill,
Ziedulla Abdullaev, Svetlana D. Pack, Sharon B. Shively, Gordon Stamp, Russell R. Lonser


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.


von Hippel-Lindau disease (VHL) is a progressive multi-system familial tumor syndrome characterized by phenotypically similar vascular tumors in the central nervous system (CNS) and viscera1. Characteristic VHL neoplasms include CNS hemangioblastomas, endolymphatic sac tumors, renal cell carcinomas (RCCs), pheochromocytomas and pancreatic cystadenomas1. VHL is caused by a germline mutation in the von Hippel-Lindau tumor suppressor gene (VHL) located on the short arm of chromosome 3 (3p25–26). Tumor development occurs after loss of the wild-type allele (loss of heterozygosity [LOH]). While this second-hit is somatic and varies between different tumors in VHL7, it takes place within a susceptible cell type in an at risk organ system during embryogenesis and results in a consistent tumor phenotype.

Shared tumor characteristics in VHL can be attributed to a decrease in the production of functional VHL protein (pVHL) in affected tumor cells. pVHL is necessary for the degradation of hypoxia inducible factors ([HIF] HIF-1α and HIF-2α), which in response to tissue hypoxia play a significant role in cellular metabolism, growth and proliferation, as well as induction of angiogenesis and erythropoiesis through the production of downstream factors (e.g., vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], erythropoietin [EPO], and endothelin [EDN1]). Data suggest that constitutively upregulated HIF activity drives the development and progression of the vascular tumors characteristically found in VHL patients.

Recently, the hemangioblast cell has been identified as giving rise to VHL-associated CNS hemangioblastomas. Hemangioblast cells are identified by the co-expression of brachyury, Flk-1, and Scl/Tal1. Fluorescence-activated cell sorting by known hemangioblast markers (Tie2hic-Kit+CD41-) in vitro yields both endothelial cells and erythrocytes. Moreover, VHL-associated tumor cells can evoke blood island formation and differentiate into erythrocytes in vitro and in vivo, as well as form endothelial cell progeny in vitro. These findings indicate that VHL-associated hemangioblastomas are not only capable of extramedullary hematopoiesis but potentially blood vessel development.

It had been hypothesized that extensive blood vessel formation in VHL-associated tumors was exclusively the result of reactive angiogenesis within a pseudo-hypoxic (pVHL deficient) cellular environment, and secondary to HIF-induced downstream factor production (VEGF, PDGF, EPO, and END1). However, the discovery of the multipotent hemangioblast as the neoplastic cell in hemangioblastomas suggested that de novo formation of new blood vessels directly through stem-like endothelial progenitor cells (hemangioblast cells) could play a role in tumor blood vessel development. To define the origin of the vasculature in VHL-associated CNS hemangioblastomas and other VHL-associated tumors, we characterized their vasculature in vitro and in vivo.

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