Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

Nicole Bechmann; Graeme Eisenhofer

doi:10.1055/a-1526-5263

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2022; 130(05): 282-289
DOI: 10.1055/a-1526-5263

Review

Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

Authors

Nicole Bechmann

¹Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

³German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Nuthetal, Germany

⁴German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Graeme Eisenhofer

¹Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Abstract

Germline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6–6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

Key words

genotype-phenotype relationships - HIF2α inhibitors - hypoxia - invasion-metastasis cascade - neuroendocrine-to-mesenchymal transition

Full Text

References

References
1 Pacak K, Tella SH. Pheochromocytoma and paraganglioma. Feingold KR, Anawalt B, Boyce A. et al. Eds. Endotext [Internet] South Dartmouth (MA): MDText.com, Inc; 2000
2 Ayala-Ramirez M, Feng L, Johnson MM. et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 2011; 96: 717-725
3 Hamidi O, Young WF, Iñiguez-Ariza NM. et al. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab 2017; 102: 3296-3305
4 Fassnacht M, Assie G, Baudin E. et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31: 1476-1490
5 Eisenhofer G, Lenders JW, Siegert G. et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 2012; 48: 1739-1749
6 Eisenhofer G, Deutschbein T, Constantinescu G. et al. Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma. Clin Chem Lab Med 2020; 59: 353-363
7 Job S, Draskovic I, Burnichon N. et al. Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma. Clin Cancer Res 2019; 25: 760-770
8 Bechmann N, Moskopp ML, Ullrich M. et al. HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas. Endocr-Relat Cancer 2020; 27: 625-640
9 Hu C-J, Wang L-Y, Chodosh LA. et al. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biology 2003; 23: 9361-9374
10 Carroll VA, Ashcroft M. Role of hypoxia-inducible factor (HIF)-1α versus HIF-2α in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 2006; 66: 6264-6270
11 Kaelin WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Molecular Cell 2008; 30: 393-402
12 Holmquist-Mengelbier L, Fredlund E, Löfstedt T. et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell 2006; 10: 413-423
13 Koh MY, Lemos R, Liu X. et al. The hypoxia-associated factor switches cells from HIF-1α-to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 2011; 71: 4015-4027
14 Shen C, Beroukhim R, Schumacher SE. et al. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov 2011; 1: 222-235
15 Toledo RA, Qin Y, Srikantan S. et al. In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr-Relat Cancer 2013; 20: 349
16 Wiesener MS, Jürgensen JS, Rosenberger C. et al. Widespread, hypoxia–inducible expression of HIF–2α in distinct cell populations of different organs. FASEB J 2003; 17: 271-273
17 Fishbein L, Leshchiner I, Walter V. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 2017; 31: 181-193
18 Cascón A, Remacha L, Calsina B. et al. Pheochromocytomas and paragangliomas: bypassing cellular respiration. Cancers 2019; 11: 683
19 Fliedner SM, Brabant G, Lehnert H. Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype. Cell Tissue Res 2018; 372: 347-365
20 Crona J, Lamarca A, Ghosal S. et al. Genotype-phenotype correlations in pheochromocytoma and paraganglioma. Endocr Relat Cancer 2019; 26: 539-550
21 Eisenhofer G, Huynh T, Pacak K. et al. Distinct gene expression profiles in norepinephrine-and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome. Endocr-Relat Cancer 2004; 11: 897-911
22 Dahia PL, Ross KN, Wright ME. et al. A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1: e8
23 Jochmanova I, Zelinka T, Widimský J. et al. HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors. Physiol Res 2014; 63: S251-S262
24 Gimenez-Roqueplo A-P, Favier J, Rustin P. et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003; 63: 5615-5621
25 Favier J, Plouin P-F, Corvol P. et al. Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am J Pathol 2002; 161: 1235-1246
26 Qin N, De Cubas AA, Garcia-Martin R. et al. Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC–associated factor X. Int J Cancer 2014; 135: 2054-2064
27 Morin A, Goncalves J, Moog S. et al. TET-mediated hypermethylation primes SDH-deficient cells for HIF2α-driven mesenchymal transition. Cell Rep 2020; 30: 4551-4566. e4557
28 Bechmann N, Poser I, Seifert V. et al. Impact of extrinsic and intrinsic hypoxia on catecholamine biosynthesis in absence or presence of HIF2α in pheochromocytoma cells. Cancers 2019; 11: 594
29 Eisenhofer G, Pacak K, Huynh T-T. et al. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr-Relat Cancer 2011; 18: 97-111
30 Eisenhofer G, Huynh T-T, Elkahloun A. et al. Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma. Am J Physiol-Endocrinol Metab 2008; 295: E1223-E1233
31 Niklasson CU, Fredlund E, Monni E. et al. Hypoxia inducible factor-2α importance for migration, proliferation, and self-renewal of trunk neural crest cells. Dev Dyn 2021; 250: 191-236
32 Pietras A, Gisselsson D, Øra I. et al. High levels of HIF-2α highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol 2008; 214: 482-488
33 Kameneva P, Artemov AV, Kastriti ME. et al. Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin. Nat Genet 2021; 1-13
34 Eisenhofer G, Timmers HJ, Lenders JW. et al. Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab 2011; 96: 375-384
35 Pamporaki C, Hamplova B, Peitzsch M. et al. Characteristics of pediatric vs adult pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 2017; 102: 1122-1132
36 Castro-Vega LJ, Buffet A, De Cubas AA. et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2014; 23: 2440-2446
37 Eisenhofer G, Lenders JW, Goldstein DS. et al. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem 2005; 51: 735-744
38 Ibanez M, Valderrama-Canales FJ, Maranillo E. et al. Human laryngeal ganglia contain both sympathetic and parasympathetic cell types. Clin Anat 2010; 23: 673-682
39 Kummer W, Habeck J-O. Chemoreceptor A-fibres in the human carotid body contain tyrosine hydroxylase and neurofilament immunoreactivity. Neuroscience 1992; 47: 713-725
40 Rao D, Peitzsch M, Prejbisz A. et al. Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma. Eur J Endocrinol 2017; 177: 103-113
41 Jiang J, Zhang J, Pang Y. et al. Sino-European differences in the genetic landscape and clinical presentation of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2020; 105: 3295-3307
42 Wurtman RJ, Axelrod J. Adrenaline synthesis: control by the pituitary gland and adrenal glucocorticoids. Science 1965; 150: 1464-1465
43 Isobe K, Nakai T, Yashiro T. et al. Enhanced expression of mRNA coding for the adrenaline-synthesizing enzyme phenylethanolamine-N-methyl transferase in adrenaline-secreting pheochromocytomas. J Urol 2000; 163: 357-362
44 Funahashi H, Imai T, Tanaka Y. et al. Discrepancy between PNMT presence and relative lack of adrenaline production in extra-adrenal pheochromocytoma. J Surg Oncol 1994; 57: 196-200
45 Toledo RA, Qin Y, Srikantan S. et al. Effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr-Relat Cancer 2013; 20: 349-359
46 Zhuang Z, Yang C, Lorenzo F. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012; 367: 922-930
47 Lorenzo FR, Yang C, Fui MNT. et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med 2013; 91: 507-512
48 Buffet A, Smati S, Mansuy L. et al. Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab 2014; 99: E369-E373
49 Pacak K, Jochmanova I, Prodanov T. et al. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol 2013; 31: 1690-1698
50 Yang C, Hong CS, Prchal JT. et al. Somatic mosaicism of EPAS1 mutations in the syndrome of paraganglioma and somatostatinoma associated with polycythemia. Hum Genome Var 2015; 2: 1-2
51 Currás-Freixes M, Piñeiro-Yañez E, Montero-Conde C. et al. PheoSeq: a targeted next-generation sequencing assay for pheochromocytoma and paraganglioma diagnostics. J Mol Diagn 2017; 19: 575-588
52 Därr R, Nambuba J, Del Rivero J. et al. Novel insights into the polycythemia–paraganglioma–somatostatinoma syndrome. Endocr-Relat Cancer 2016; 23: 899-908
53 Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15: 178-196
54 Loriot C, Domingues M, Berger A. et al. Deciphering the molecular basis of invasiveness in Sdhb-deficient cells. Oncotarget 2015; 6: 32955-32965
55 Loriot C, Burnichon N, Gadessaud N. et al. Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. J Clin Endocrinol Metab 2012; 97: E954-E962
56 Calsina B, Castro-Vega LJ, Torres-Pérez R. et al. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics 2019; 9: 4946-4958
57 Letouzé E, Martinelli C, Loriot C. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 2013; 23: 739-752
58 Castro-Vega LJ, Letouzé E, Burnichon N. et al. Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun 2015; 6: 1-9
59 De Cubas AA, Korpershoek E, Inglada-Pérez L. et al. DNA methylation profiling in pheochromocytoma and paraganglioma reveals diagnostic and prognostic markers. Clin Cancer Res 2015; 21: 3020-3030
60 Gieldon L, William D, Hackmann K. et al. Optimizing genetic workup in pheochromocytoma and paraganglioma by integrating diagnostic and research approaches. Cancers 2019; 11: 809
61 Shankar J, Messenberg A, Chan J. et al. Pseudopodial actin dynamics control epithelial-mesenchymal transition in metastatic cancer cells. Cancer Res 2010; 70: 3780-3790
62 Lenders JW, Kerstens MN, Laurence A. et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the working group on endocrine hypertension of the european society of hypertension. J Hypertens 2020; 38: 1443-1456
63 Seifert V, Richter S, Bechmann N. et al. HIF2alpha-associated pseudohypoxia promotes radioresistance in pheochromocytoma: insights from 3D models. Cancers 2021; 13: 385
64 Luo W, Wang Y. Hypoxia mediates tumor malignancy and therapy resistance. Adv Exp Med Biol 2019; 1136: 1-18
65 Scheuermann TH, Tomchick DR, Machius M. et al. Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci 2009; 106: 450-455
66 Rogers JL, Bayeh L, Scheuermann TH. et al. Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor. J Med Chem 2013; 56: 1739-1747
67 Courtney KD, Infante JR, Lam ET. et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol 2018; 36: 867-874
68 Xu R, Wang K, Rizzi JP. et al. 3-[(1 S, 2 S, 3 R)-2, 3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl] oxy-5-fluorobenzonitrile (PT2977), a hypoxia-inducible factor 2α (HIF-2α) inhibitor for the treatment of clear cell renal cell carcinoma. J Med Chem 2019; 62: 6876-6893
69 Strowd R, Ellingson B, Wen P. et al. ACTR-15. Safety and preliminary activity of PT2385, a first-in-class HIF2-alpha inhibitor, planned interim analysis of an open label, single-arm phase II study in patients with recurrent glioblastoma. Neuro-Oncol 2018; 20: vi14-vi14
70 Chen W, Hill H, Christie A. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 2016; 539: 112-117
71 Courtney KD, Ma Y, de Leon AD. et al. HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clin Cancer Res 2020; 26: 793-803
72 Persson CU, von Stedingk K, Fredlund E. et al. ARNT-dependent HIF-2 transcriptional activity is not sufficient to regulate downstream target genes in neuroblastoma. Exp Cell Res 2020; 388: 111845
73 Gordan JD, Bertout JA, Hu C-J. et al. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 2007; 11: 335-347
74 Gordan JD, Thompson CB, Simon MCHIF. and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007; 12: 108-113