Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome

Abstract

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 norepinephrineand 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-2a, 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-2a in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

“…We also show that the tumors with EPAS1 mutations have a very low expression of PNMT, encoding the enzyme PNMT which catalyzes the methylation of norepinephrine to form epinephrine. This is in agreement with the loss of PNMT expression in other Cluster 1 tumors as compared with Cluster 2 tumors, which have a high expression, resulting in high epinephrine levels (Eisenhofer et al 2004). Furthermore, the five tumors with EPAS1 mutations clustered together with hereditary VHL and SDH cases, supporting the hypothesis that the mutations have a role in the disease by inducing a similar pseudo-hypoxic response.…”

“…This changed when somatic NF1 mutations were revealed in about 20-25% of sporadic pheochromocytomas (Burnichon et al 2012, Welander et al 2012, but still the majority of sporadic tumors remain unexplained. Studies of gene expression have revealed that pheochromocytomas and paragangliomas can be divided into two groups: VHL-and SDHx-mutated tumors form one cluster (Cluster 1) with a hypoxia-related transcription signature, whereas RET/NF1/TMEM127/MAX-mutated tumors form another cluster (Cluster 2) and display transcription profiles characterized by the activation of kinase signaling pathways (Eisenhofer et al 2004, Dahia et al 2005, Dahia 2014). Sporadic tumors cluster into either of the two distinct groups, instead of forming clusters of their own, indicating that similar molecular mechanisms are involved.…”

Regulation of microRNA expression by HMGA1 proteins

“…The modulation of its expression has been revealed in numerous developmental, physiological and pathological processes. Recently, STC1 has also been reported to be induced in a variety of tumors including the breast (McCudden et al, 2004), colon (Gerritsen et al, 2002), ovary (Ismail et al, 2000), lung cancer (Garber et al, 2001), thyroid medullary carcinoma (Watanabe et al, 2002), hepatocarcinoma (Okabe et al, 2001), pheochromocytoma (Eisenhofer et al, 2004), neuroblastoma (Wong et al, 2002), osteosarcoma and fibrosarcoma (Jellinek et al, 2000). The possible use of STC1 expression levels for the diagnosis of human breast, hepatocellular and colorectal cancer has also been proposed (Fujiwara et al, 2000;Wascher et al, 2003).…”

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

“…Microarray studies of genome-wide mRNA expression have revealed that hereditary PCCs and PGLs cluster into two distinct groups based on their transcription profile: tumors with VHL mutations resemble those with mutations in any of the SDHx genes and display a different transcription profile compared to tumors caused by RET or NF1 mutations (Eisenhofer et al 2004, Dahia et al 2005b. By unsupervised hierarchical cluster analysis of sporadic and hereditary PCCs, Dahia et al (2005b) could identify two dominant expression clusters, where the first cluster contained all VHL-and SDHx-mutant tumors whereas the second contained all RET-and NF1-mutant tumors.…”