Regulation of catecholamine synthesizing enzyme gene expression in human pheochromocytoma.

Abstract

This issue of the European Journal of Endocrinology contains an important report investigating the expression of the mRNAs coding for catecholamine synthesizing enzymes in human pheochromocytomas (1). Despite all efforts to characterize these tumors by molecular biological techniques and to study the expression of various growth factors and their receptors, investigations into the genuine enzymes have so far been surprisingly scarce. This and other studies clearly suggest that this methodological approach cannot only be used to further characterize the genomic properties with regard to the expression of the various enzymes in these tumors, but also to yield prognostic criteria in terms of benign versus malignant pheochromocytoma. In order to fully appreciate the pathophysiological relevance and implications of this approach, it is mandatory to characterize the nature of this tumor and basic mechanisms of catecholamine biosynthesis. I shall thus use this editorial to briefly review the clinical genetics and aspects of pheochromocytoma, followed by novel general aspects of catecholamine enzyme regulation, as well as synthesis, storage and secretion of these hormones, and finally discuss some of the data available on catecholamine synthesizing enzyme mRNA expression in human pheochromocytomas and their possible clinical relevance. The pheochromocytoma represents a catecholamine secreting tumor that can arise both from intraand extraadrenal chromaffin cells. The term paraganglioma describes a subgroup of those tumors which originate in extraadrenal chromaffin cells. These cells are of neuroectodermal origin and thus part of the so-called diffuse neuroendocrine system. This embryogenetic basis also explains the association of a pheochromocytoma with other disorders sharing this origin. There are few data on the incidence and prevalence of this tumor; a prevalence between 0.2 and 0.4% in patients with diastolic hypertension is suggested. A pheochromocytoma can be classified according to various categories. A major criterion is the sporadic versus familial appearance; another is represented by localization (intraversus extraadrenal). Finally, benign and malignant pheochromocytomas have to be differentiated. Approximately 10% of all pheochromocytomas of the adult reveal an extraadrenal localization, while this number appears to be higher in children, with approximately 35%. The majority of pheochromocytomas (approximately 90%) are of sporadic nature; familiarity has in particular been observed when the following diseases are either underlying or coexisting: multiple endocrine neoplasia (MEN) type 2 a/b, von Hippel–Lindau syndrome (vHLS) and neurofibromatosis type I (NFI). In addition to NFI, tuberosis sclerosis and Sturge–Weber disease are of neuroectodermal origin and associated with pheochromocytoma. As mentioned, the potential malignancy of these tumors represents a major clinical problem. Approximately 20% of all pheochromocytomas will eventually be malignant. The most strict criterion for malignancy is the appearance of metastases in organs that otherwise do not contain chromaffin cells (2). The pathogenesis of pheochromocytoma is still unclear. It is only the pheochromocytoma within the context of MEN, vHLS or NF that possesses a characterized molecular genetic background. In MEN 2a/b, mutations of the RET proto-oncogene and chromosome 10 have been very well described. This oncogene belongs to the group of tyrosine kinase receptor coding oncogenes, which can be activated by DNA rearrangement (3). The tyrosine kinase then functions as a receptor for the glial cell-derived neurotrophic factor (GDNF) and GDNF–receptor complex. The vHLS also represents a hereditary disease, which is characterized by the appearance of a number of benign and malignant tumors. The leading clinical characteristics are angioblastomas, retinal angiomas, renal cell tumors and pheochromocytomas, the last of these occurring with a frequency of 15 to 25%. The vHLS is further differentiated into type 1, type 2a and type 2b, where pheochromocytoma is associated with types 2a and b. The vHLS suppressor gene is located on chromosome 3p 25–26. In NFI, a pheochromocytoma is observed in approximately 5% of cases; vice versa in 1 to 2% of all cases diagnosis of a pheochromocytoma will eventually also lead to the diagnosis of NFI. The NFI gene codes for the protein neurofibromin, which stimulates the GTPase activity of p21 ras in vitro. It is thus conceivable that signal transduction will be induced via this protein. The NFI gene also most likely represents a tumor suppressor gene with the mutated gene located on chromosome 17. European Journal of Endocrinology (1998) 138 363–367 ISSN 0804-4643