Developmentally Arrested Basket/Stellate Cells in Postnatal Human Brain as Potential Tumor Cells of Origin for Cerebellar Hemangioblastoma in von Hippel-Lindau Patients

Authors

Sharon Baughman Shively, From the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Nancy A. Edwards, From the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Tobey J. MacDonald, Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
Kory R. Johnson, Bioinformatics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Natalia M. Diaz-Rodriguez, From the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Marsha J. Merrill, From the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Alexander O. Vortmeyer, From the Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Document Type

Journal Article

Publication Date

10-18-2022

Journal

Journal of neuropathology and experimental neurology

Volume

81

Issue

11

DOI

10.1093/jnen/nlac073

Keywords

Developmentally arrested basket/stellate cells; Hemangioblastoma; Paired box 2 (PAX2); Tumor suppressor syndrome; VHL human cerebellum tumor cell of origin; von Hippel-Lindau (VHL) disease

Abstract

von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer disorder caused by a germline mutation in the VHL tumor suppressor gene. Loss of the wild-type allele results in VHL deficiency and the potential formation of cerebellar hemangioblastomas, which resemble embryonic hemangioblast proliferation and differentiation processes. Multiple, microscopic, VHL-deficient precursors, termed developmentally arrested structural elements (DASEs), consistently involve the cerebellar molecular layer in VHL patients, indicating the tumor site of origin. Unlike hemangioblastomas, however, cerebellar DASEs do not express brachyury, a mesodermal marker for hemangioblasts. In this study, neuronal progenitors occupying the molecular layer were investigated as tumor cells of origin. By immunohistochemistry, cerebellar DASEs and hemangioblastomas lacked immunoreactivity with antibody ZIC1 (Zic family member 1), a granule cell progenitor marker with concordance from oligonucleotide RNA expression array analyses. Rather, cerebellar DASEs and hemangioblastomas were immunoreactive with antibody PAX2 (paired box 2), a marker of basket/stellate cell progenitors. VHL cerebellar cortices also revealed PAX2-positive cells in Purkinje and molecular layers, resembling the histological and molecular development of basket/stellate cells in postnatal non-VHL mouse and human cerebella. These data suggest that VHL deficiency can result in the developmental arrest of basket/stellate cells in the human cerebellum and that these PAX2-positive, initiated cells await another insult or signal to form DASEs and eventually, tumors.

APA Citation

Shively, Sharon Baughman; Edwards, Nancy A.; MacDonald, Tobey J.; Johnson, Kory R.; Diaz-Rodriguez, Natalia M.; Merrill, Marsha J.; and Vortmeyer, Alexander O., "Developmentally Arrested Basket/Stellate Cells in Postnatal Human Brain as Potential Tumor Cells of Origin for Cerebellar Hemangioblastoma in von Hippel-Lindau Patients" (2022). GW Authored Works. Paper 1761.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1761

Department

School of Medicine and Health Sciences Student Works