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A Developmental Perspective on Paragangliar Tumorigenesis.

Lavinia Vittoria Lotti1, Simone Vespa2,3, Mattia Russel Pantalone4

  • 1Department of Experimental Medicine, "La Sapienza" University, Viale Regina Elena 324, 00161 Rome, Italy. laviniavittoria.lotti@uniroma1.it.

Cancers
|March 1, 2019
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Summary

Paraganglioma arises from a multipotent stem cell, forming aberrant vascular and neural tissues. This is supported by molecular data and xenograft models showing self-organization into tumor structures.

Keywords:
angiogenesiscarotid bodymitochondrianeural crestneurogenesisparagangliomastem-like tumor cellsvasculogenesisxenograft

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Area of Science:

  • Oncology
  • Stem Cell Biology
  • Molecular Pathogenesis

Background:

  • Paragangliomas are rare neuroendocrine tumors.
  • Their cellular origin and organization remain incompletely understood.
  • Existing models do not fully explain the observed vascular and neural components.

Purpose of the Study:

  • To propose a unifying model for paraganglioma development.
  • To investigate the cellular origin and tissue organization in head and neck paragangliomas.
  • To elucidate the molecular mechanisms driving paraganglioma formation.

Main Methods:

  • Immunomorphological and molecular analyses of human paragangliomas.
  • Characterization of derived cell cultures.
  • Establishment and analysis of xenograft models.
  • Assessment of NOTCH signaling and microRNA expression.

Main Results:

  • Paraganglioma tissue comprises neoplastic vascular and neural cells originating from a multipotent mesenchymal-like stem cell.
  • Shared immature vasculo-neural markers link vascular and neural tumor compartments.
  • Constitutive NOTCH pathway activation and microRNA loss (microRNA-200s, -34s) characterize the immature phenotype.
  • Neuroepithelial cells exhibit severe mitochondrial alterations.
  • Xenograft models show mesenchymal cells forming vascular networks and then neuroepithelial clusters, a process inhibited by imatinib.

Conclusions:

  • Paraganglioma is an aberrant tissue organized from a multipotent progenitor.
  • The pseudohypoxic molecular signature and neural crest origin support this model.
  • Understanding this organization provides insights into tumor pathogenesis and potential therapeutic targets.