Target Discovery Institute, University of Oxford, Oxford, UK.
Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
Endocr Relat Cancer. 2021 Oct 18;28(12):757-772. doi: 10.1530/ERC-21-0211.
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.
尽管 HIF 羟化酶系统在细胞氧感应和肿瘤缺氧中具有普遍作用，但该途径中基因的癌症相关突变，包括 PHD2、PHD1 和 EPAS1（编码 HIF-2α），具有高度的组织特异性，仅在假性缺氧嗜铬细胞瘤和副神经节瘤（PPGL）中观察到，而在其他肿瘤中很少观察到。为了了解这一悖论，并深入了解假性缺氧 PPGL 的发病机制，我们使用 TH 限制型 Cre 重组酶构建了肾上腺髓质中主要 HIF 脯氨酰羟化酶 Phd2 失活的小鼠。对这些动物的研究揭示了一种与假性缺氧 PPGL 非常相似的基因表达模式。空间分辨分析表明，两种截然不同的基因表达模式在肾上腺髓质细胞中呈二元分布。Phd2 的失活导致这种分布向 Pnmt-/Hif-2α+/Rgs5+ 群体发生明显转变。这与肾上腺发育的形态异常有关，包括肾上腺皮质内和肾上腺外异位的 TH+细胞。这些变化通过 Phd2 与 Hif-2α的联合失活而消除，但不通过 Hif-1α的失活而消除。然而，它们不能通过成年期 Phd2 的失活来重现，这表明它们是由于该途径在肾上腺发育过程中的失调而产生的。结合假性缺氧 PPGL 表现出明显高遗传力的临床观察结果，我们的研究结果表明，这种类型的肿瘤可能是由于 PHD2/HIF-2α 途径的组织特异性作用失调而引起的，该途径影响早期生命的肾上腺发育，并为相关过程的研究提供了模型。
