The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

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....

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Main Authors: Song Peng, Jun Zhang, Xintao Tan, Yiqiang Huang, Jing Xu, Natalie Silk, Dianzheng Zhang, Qiuli Liu, Jun Jiang
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-11-01
Series:Frontiers in Endocrinology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fendo.2020.586857/full
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author Song Peng
Jun Zhang
Xintao Tan
Yiqiang Huang
Jing Xu
Natalie Silk
Dianzheng Zhang
Qiuli Liu
Jun Jiang
author_facet Song Peng
Jun Zhang
Xintao Tan
Yiqiang Huang
Jing Xu
Natalie Silk
Dianzheng Zhang
Qiuli Liu
Jun Jiang
author_sort Song Peng
collection DOAJ
description 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.
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spelling doaj.art-36897ea4881a47fba02686412f9ab1fe2022-12-22T00:23:26ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922020-11-011110.3389/fendo.2020.586857586857The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/ParagangliomaSong Peng0Jun Zhang1Xintao Tan2Yiqiang Huang3Jing Xu4Natalie Silk5Dianzheng Zhang6Qiuli Liu7Jun Jiang8Department of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United StatesDepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United StatesDepartment of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of Urology, Daping Hospital, Army Medical University, Chongqing, ChinaPheochromocytomas 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.https://www.frontiersin.org/articles/10.3389/fendo.2020.586857/fullpheochromocytomasparagangliomasVHLHIFmetabolisminhibitor
spellingShingle Song Peng
Jun Zhang
Xintao Tan
Yiqiang Huang
Jing Xu
Natalie Silk
Dianzheng Zhang
Qiuli Liu
Jun Jiang
The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
Frontiers in Endocrinology
pheochromocytomas
paragangliomas
VHL
HIF
metabolism
inhibitor
title The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
title_full The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
title_fullStr The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
title_full_unstemmed The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
title_short The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
title_sort vhl hif axis in the development and treatment of pheochromocytoma paraganglioma
topic pheochromocytomas
paragangliomas
VHL
HIF
metabolism
inhibitor
url https://www.frontiersin.org/articles/10.3389/fendo.2020.586857/full
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