Von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells

Deric M. Park, Zhengping Zhuang, Ling Chen, Nicholas Szerlip, Irina Maric, Jie Li, Taesung Sohn, Stephanie H. Kim, Irina A. Lubensky, Alexander Vortmeyer, Griffin P. Rodgers, Edward H. Oldfield, Russell R. Lonser

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Abstract

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. Methods and Findings: 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 mesodermderived, 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.

Original languageEnglish (US)
Pages (from-to)333-341
Number of pages9
JournalPLoS Medicine
Volume4
Issue number2
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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Hemangioblastoma
von Hippel-Lindau Disease
Hemangioblasts
Central Nervous System
Neoplasms
Leukemia
Stem Cells
Brain Stem Neoplasms
Spinal Cord Neoplasms
Erythropoietin Receptors
Cellular Microenvironment
Antigen Receptors
Tissue Distribution
Erythropoietin
Hematopoietic Stem Cells
Cerebellum
Vascular Endothelial Growth Factor A
Cell Differentiation
Alleles

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Park, D. M., Zhuang, Z., Chen, L., Szerlip, N., Maric, I., Li, J., ... Lonser, R. R. (2007). Von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Medicine, 4(2), 333-341. https://doi.org/10.1371/journal.pmed.0040060

Von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. / Park, Deric M.; Zhuang, Zhengping; Chen, Ling; Szerlip, Nicholas; Maric, Irina; Li, Jie; Sohn, Taesung; Kim, Stephanie H.; Lubensky, Irina A.; Vortmeyer, Alexander; Rodgers, Griffin P.; Oldfield, Edward H.; Lonser, Russell R.

In: PLoS Medicine, Vol. 4, No. 2, 01.02.2007, p. 333-341.

Research output: Contribution to journalArticle

Park, DM, Zhuang, Z, Chen, L, Szerlip, N, Maric, I, Li, J, Sohn, T, Kim, SH, Lubensky, IA, Vortmeyer, A, Rodgers, GP, Oldfield, EH & Lonser, RR 2007, 'Von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells', PLoS Medicine, vol. 4, no. 2, pp. 333-341. https://doi.org/10.1371/journal.pmed.0040060
Park, Deric M. ; Zhuang, Zhengping ; Chen, Ling ; Szerlip, Nicholas ; Maric, Irina ; Li, Jie ; Sohn, Taesung ; Kim, Stephanie H. ; Lubensky, Irina A. ; Vortmeyer, Alexander ; Rodgers, Griffin P. ; Oldfield, Edward H. ; Lonser, Russell R. / Von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. In: PLoS Medicine. 2007 ; Vol. 4, No. 2. pp. 333-341.
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AU - Zhuang, Zhengping

AU - Chen, Ling

AU - Szerlip, Nicholas

AU - Maric, Irina

AU - Li, Jie

AU - Sohn, Taesung

AU - Kim, Stephanie H.

AU - Lubensky, Irina A.

AU - Vortmeyer, Alexander

AU - Rodgers, Griffin P.

AU - Oldfield, Edward H.

AU - Lonser, Russell R.

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N2 - 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. Methods and Findings: 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 mesodermderived, 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.

AB - 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. Methods and Findings: 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 mesodermderived, 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.

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