von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells.
BACKGROUND
To 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.


RESULTS
A 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.


CONCLUSIONS
The 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.
Park
Deric M
DM
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
Zhuang
Zhengping
Z
Chen
Ling
L
Szerlip
Nicholas
N
Maric
Irina
I
Li
Jie
J
Sohn
Taesung
T
Kim
Stephanie H
SH
Lubensky
Irina A
IA
Vortmeyer
Alexander O
AO
Rodgers
Griffin P
GP
Oldfield
Edward H
EH
Lonser
Russell R
RR
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D018826:CD13 Antigens / Q000235:genetics; D015550:Cell Degranulation; D002528:Cerebellar Neoplasms / Q000150:complications / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D018325:Hemangioblastoma / Q000150:complications / Q000473:pathology* / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000473:pathology*; D012334:RNA, Neoplasm / Q000235:genetics; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D006623:von Hippel-Lindau Disease / Q000150:complications* / Q000473:pathology
D012334:RNA, Neoplasm; D018826:CD13 Antigens