A Developmental Perspective on Paragangliar Tumorigenesis

Cancers
Lavinia Vittoria LottiRenato Mariani-Costantini

Abstract

In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in the molecular pathogenesis of the disease, is in harmony with the neural crest origin of the paraganglia, and is strongly supported by the physiological model of carotid body hyperplasia. Our immunomorphological and molecular studies of head and neck paragangliomas demonstrate in all cases relationships between the vascular and the neural tumor compartments, that share mesenchymal and immature vasculo-neural markers, conserved in derived cell cultures. This immature, multipotent phenotype is supported by constitutive amplification of NOTCH signaling genes and by loss of the microRNA-200s and -34s, which control NOTCH1, ZEB1, and PDGFRA in head and neck paraganglioma cells. Importantly, the neuroepithelial component is distinguished by extreme mitochondrial alterations, associated with collapse of the ΔΨm. Finally, our xenograft models of head and neck paraganglioma demonstrate that mesenchymal-like cells first give rise to ...Continue Reading

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Citations

Sep 22, 2019·Cancers·Karel Pacak, David Taïeb
Mar 12, 2020·Frontiers in Endocrinology·Laura D ScribaCharlotte Steenblock
Aug 30, 2020·Disease Models & Mechanisms·Éva SaskőiKrisztina Takács-Vellai
Apr 16, 2021·SAGE Open Medicine·Robin OsofskyMuhammad Ali Rana

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Methods Mentioned

BETA
electron microscopy
xenografts
reverse transcription quantitative PCR
transfection
Xenograft

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