Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome
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Pheochromocytomas in von Hippel–Lindau (VHL) syndrome produce exclusively norepinephrine, whereas those in multiple endocrine neoplasia type 2 (MEN 2) produce epinephrine. This study examined the pathways activated in VHL-associated pheochromocytomas by comparing gene expression profiles in VHL and MEN 2 tumors in relationship to profiles in sporadic norepinephrine- and epinephrine-producing tumors. Larger and more distinct differences in gene expression among hereditary than sporadic tumors indicated the importance of the underlying mutation to gene expression profiles. Many of the genes over-expressed in VHL compared with MEN 2 tumors were clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter, vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and its coreceptor, neuropilin-1. Other up-regulated genes, such as connective tissue growth factor, cysteine-rich 61, matrix metalloproteinase 1, vascular endothelial cadherin, tenascin C, stanniocalcin 1, and cyclooxygenases 1 and 2 are known to be involved in VEGF-regulated angiogenesis. Shared differences in expression of subsets of genes in norepinephrine- versus epinephrine-producing hereditary and sporadic pheochromocytomas indicated other differences in gene expression that may underlie the biochemical phenotype. Over-expression of the hypoxia-inducible transcription factor, HIF-2α, in norepinephrine-predominant sporadic and VHL tumors compared with epinephrine-producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype. The findings fit with the known expression of HIF-2α in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.
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The tumorigenesis of pheochromocytomas, paragangliomas, and neuroblastomas seems to involve aberrant HIF-2 signaling, resulting in pseudohypoxic phenotypes linked to disseminated disease.
“Interestingly, the tumorigenesis of these closely related tumors seems to involve aberrant HIF-2 signaling, resulting in pseudohypoxic phenotypes linked to disseminated disease (Eisenhofer et al., 2004;Pietras et al., 2008;Favier et al., 2009).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Eisenhofer et al., 2004
The Discussion (page unavailable) supports a possible role for HIF-2α-mediated, hypoxia-driven angiogenic processes in VHL-associated pheochromocytoma development, while cautioning that HIF-2α may not be central to every VHL-associated case. It does not establish the same mechanism for paragangliomas or neuroblastomas, or link that mechanism to disseminated disease. (LLM, conf=0.87)
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Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
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Sorted by citations
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687 · see citing works
“Cluster 1 includes HIF2A-, VHL-, and SDHx-related tumors and is characterized by expression of genes involved in hypoxic signaling and high expression of HIF-2α itself (Eisenhofer et al., 2004; Lopez-Jimenez et al., 2010).”
BackgroundThe Warburg effect is genetically determined in inherited pheochromocytomas
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- Authors
- Eisenhofer, G., Huynh, T.-T., Pacak, K., Brouwers, F. M., Walther, M. M., Linehan, W. M., Munson, P. J., Mannelli, M., Goldstein, D. S., & Elkahloun, A. G.
- Affiliations
- National Institutes of Health (US)
- 1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
- Venue
- Endocrine-Related Cancer
- Publisher
- Bioscientifica
- Published
- 2004-12-01
- Volume
- 11
- Issue
- 4
- Pages
- 897-911
- ISSN
- 1351-0088 (ISSN-L)
- 1479-6821
- OpenAlex
- W2115406537
- Cited by
- 207
- References
- 2
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 8 · 2023: 12 · 2022: 8 · 2021: 7 · 2020: 7 · 2019: 11 · 2018: 10 · 2017: 9 · 2016: 10 · 2015: 15 · 2014: 16 · 2013: 16 · 2012: 13
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Related Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Keywords
- pheochromocytoma, von Hippel-Lindau disease, multiple endocrine neoplasia type 2, gene expression profiles, hypoxia, angiogenesis, vascular endothelial growth factor, HIF-2α, noradrenergic phenotype, tumor suppressor mutations
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adolescent, Adrenal Gland Neoplasms, Adult, Hypoxia, Child, Epinephrine, Female, von Hippel-Lindau Disease, Humans, Male, Middle Aged, Norepinephrine, Pheochromocytoma, Multiple Endocrine Neoplasia Type 2a, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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