Abstract
Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.
Highlights
Pheochromocytoma (PHEO) and paraganglioma (PGL) are tumors arising from chromaffin cells that derive from the embryonic neural crest
Lower CAT concentration in PGL was associated with tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA lower abundance; TH was downregulated by 2.6 fold P = 0.04 and PNMT by 10.5 fold P
Tumors for CAT content and secretion (Fig 2A and 2B), PHEO were further subdivided into two groups; PHEO were considered as noradrenergic (NorAd PHEO) when the E concentration in tumor tissue was below 10% of total CAT (NE+E), and tumors with E concentration above 10% of total CAT were termed as mixed PHEO (Table 1) as previously published [12]
Summary
Pheochromocytoma (PHEO) and paraganglioma (PGL) are tumors arising from chromaffin cells that derive from the embryonic neural crest. PHEO are located within the adrenal medulla and PGL ( formerly known as extraadrenal pheochromocytoma) are found in the sympathetic and parasympathetic ganglia [2]. PGL are more likely to develop metastasis with an incidence rate of approximately 10% of total PHEO/PGL cases. Both types of tumors produce and usually secrete larger amounts of catecholamine (CAT) than the adrenal medulla, due to an up-regulation of tyrosine hydroxylase (TH; EC 1.14.16.2) and dopamine β-hydroxylase (DBH, EC 1.14.17.1) the main enzymes responsible for CAT synthesis. PNMT appears to be down regulated in a large number of PHEO, except in E-secreting tumors. PNMT downregulation has been attributed to dysregulation in hormone and transcription factor concentration that include glucocorticoids (GC) carried from adjacent cortical cells to medulla by the adrenal portal system [6,7,8,9,10,11,12]
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