Abstract
Despite a general role for the HIF hydroxylase system in cellular oxygen sensing and tumour hypoxia, cancer-associated mutations of genes in this pathway, including PHD2, PHD1, EPAS1 (encoding HIF-2α) are highly tissue-restricted, being observed in pseudohypoxic pheochromocytoma and paraganglioma (PPGL) but rarely, if ever, in other tumours. In an effort to understand that paradox and gain insights into the pathogenesis of pseudohypoxic PPGL, we constructed mice in which the principal HIF prolyl hydroxylase, Phd2, is inactivated in the adrenal medulla using TH-restricted Cre recombinase. Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL. Spatially resolved analyses demonstrated a binary distribution of two contrasting patterns of gene expression among adrenal medullary cells. Phd2 inactivation resulted in a marked shift in this distribution towards a Pnmt−/Hif-2α+/Rgs5+ population. This was associated with morphological abnormalities of adrenal development, including ectopic TH+ cells within the adrenal cortex and external to the adrenal gland. These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α. However, they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development. Together with the clinical observation that pseudohypoxic PPGL manifests remarkably high heritability, our findings suggest that this type of tumour likely arises from dysregulation of a tissue-restricted action of the PHD2/HIF-2α pathway affecting adrenal development in early life and provides a model for the study of the relevant processes.
Highlights
Pheochromocytoma and paraganglioma (PPGL) are tumours of the autonomic paraganglia that arise in diverse anatomical locations from the skull base to the pelvis
In an attempt to shed light on these paradoxical findings and better understand the role of activation of hypoxia-inducible factor (HIF) pathways in the adrenal medulla (AM), we have examined the effects of inactivation of the principal HIF prolyl hydroxylase Phd2 in the AM, using Cre recombinase restricted by the tyrosine hydroxylase (TH) promoter, in the mouse
Since pseudohypoxic PPGLs have a characteristic gene expression profile, we first sought to test whether and to what extent this was mimicked by Phd2 inactivation in the AM
Summary
Pheochromocytoma and paraganglioma (PPGL) are tumours of the autonomic paraganglia that arise in diverse anatomical locations from the skull base to the pelvis Those found within the adrenal glands (AGs) are known as pheochromocytoma (PCC) and those in extra-adrenal structures including the carotid body are commonly termed paraganglioma (PGL). Molecular analysis of these tumours has revealed a number of subtypes or clusters, with distinct patterns of gene expression within the tumour being associated with different groups of tumourassociated mutations. They express three closely related isoforms of the HIF prolyl hydroxylase enzymes (PHD1, PHD2 and PHD3, otherwise known as EGLN2, EGLN1 and EGLN3), of which PHD2 is the most abundant and important regulator of HIF
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