Hypoxia and pheochromocytoma/paraganglioma have a long common history. Since the description, almost 40 years ago, of an increased incidence of head and neck paragangliomas in chronic hypoxia, discoveries on oxygen-sensing and on hereditary paraganglioma in the beginning of years 2000 provided the proof of concept of a strong link between these neuroendocrine tumors and the hypoxic pathway. It was demonstrated that both SDH and VHL genes mutations lead to the abnormal stabilization and activation of hypoxia-inducible factors, and to the subsequent regulation of multiple target genes, the products of which are implicated in proliferation, apoptosis, angiogenesis, energy metabolism or invasiveness and metastases. Altogether, physiological, genetic, cellular and molecular data collected over years all point to a central role of the hypoxic or pseudohypoxic pathway in pheochromocytoma and paraganglioma tumorigenesis.
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