Date Published: February 13, 2007
Publisher: Public Library of Science
Author(s): Deric M Park, Zhengping Zhuang, Ling Chen, Nicholas Szerlip, Irina Maric, Jie Li, Taesung Sohn, Stephanie H Kim, Irina A Lubensky, Alexander O Vortmeyer, Griffin P Rodgers, Edward H Oldfield, Russell R Lonser, Robert J Weil
Abstract: BackgroundTo determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we characterized and differentiated neoplastic cells from hemangioblastomas removed from VHL patients.Methods and FindingsA total of 31 CNS hemangioblastomas from 25 VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown, and differentiated into multiple lineages. Resected hemangioblastomas were located in the cerebellum (11 tumors), brainstem (five tumors), and spinal cord (15 tumors). Consistent with an embryologically derived hemangioblast, the neoplastic cells demonstrated coexpression of the mesodermal markers brachyury, Flk-1 (vascular endothelial growth factor-2), and stem cell leukemia (Scl). The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin, and erythropoietin receptor. Under specific microenvironments, neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic, and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin.ConclusionsThe neoplastic cell of origin for CNS hemangioblastomas in VHL patients is the mesoderm-derived, embryologically arrested hemangioblast. The hematopoietic and endothelial differentiation potential of these cells can be reactivated under suitable conditions. These findings may also explain the unique tissue distribution of tumor involvement.
Partial Text: von Hippel-Lindau disease (VHL) is an autosomal dominant neoplasia syndrome resulting from a germline mutation in the VHL tumor suppressor gene on the short arm of Chromosome 3 . VHL has an approximate prevalence of one in 39,000 and over 90% penetrance by 65 years of age [2,3]. Germline mutations in the VHL gene lead to the development of a number of benign or malignant tumors and cysts in multiple organ systems . Affected individuals may develop central nervous system (CNS) tumors, including hemangioblastomas and endolymphatic sac tumors [4–7]. Visceral manifestations include renal cysts and carcinomas, pheochromocytomas, pancreatic cysts, and neuroendocrine tumors, as well as epididymal and broad ligament cystadenomas [4,8–10].
Identification of the cell of origin in tumors will improve understanding of their pathobiology and treatment. For familial tumor suppressor syndromes, it may also explain the unique tissue distribution of tumor involvement. We found that the neoplastic cells of origin in CNS hemangioblastomas from VHL patients are derived from embryologically arrested mesoderm cells and are hemangioblasts with hematopoietic and vasculogenic (endothelial cell) potential. These cells retain their multipotent differentiation ability and are able to develop into hematopoietic and endothelial progenies. The identification of the cell of origin of this tumor enhances understanding of the biological basis and tumor distribution of this familial tumor suppressor syndrome and may provide therapeutic opportunities.