The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma.
The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma.
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DOI：
10.3389/fendo.2020.586857
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发表时间：
2020
影响因子：
5.2
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Peng S;Zhang J;Tan X;Huang Y;Xu J;Silk N;Zhang D;Liu Q;Jiang J
嗜铬细胞瘤和副神经节瘤（PPGL）是一种罕见的神经内分泌肿瘤，起源于肾上腺髓质（PCC）或肾上腺外交感神经或副交感神经副神经节（PGL）的嗜铬细胞。大约40%的PPGL是由种系突变引起的，因此它们具有高度的遗传性。尽管一组超过20个基因中的任何一个的功能障碍都可能导致PPGL，但参与VHL/HIF轴的基因（包括PHD、VHL、HIF-2A（EPAS 1）和SDHX）的突变在PPGL中更常见。多种证据表明，假性缺氧在PPGL的肿瘤发生中起着至关重要的作用，因此PPGL也被称为代谢性疾病。然而，VHL/HIF介导的假性缺氧和PPGL细胞中的代谢紊乱之间的相互作用还没有很好地定义。在这篇综述中，我们将首先讨论VHL/HIF轴和该轴的遗传改变。然后，我们将剖析VHL/HIF轴驱动的PPGL发病机制的潜在机制，特别注意VHL/HIF轴和癌细胞代谢之间的相互作用。最后，我们将总结目前可用的化合物/药物靶向这一轴可能被用作PPGL治疗，以及其潜在的药理学机制。本综述的总体目标是更好地了解VHL/HIF轴在PPGLs发展中的作用，建立更准确的PPGLs诊断工具，并为有效治疗转移性PPGLs铺平道路。
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.
影响因子：
4.6
作者：
Kim HC;Lee JS;Kim SH;So HS;Woo CY;Lee JL
通讯作者：
Lee JL