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Expression of Trophic Peptides and Their Receptors in Chromaffin Cells Expression of Trophic Peptides and Their Receptors in Chromaffin Cells and Pheochromocytoma Erwan Thouënnon, Alice Pierre, Laurent Yon, Youssef Anouar To cite this version: Erwan Thouënnon, Alice Pierre, Laurent Yon, Youssef Anouar. Expression of Trophic Peptides and Their Receptors in Chromaffin Cells and Pheochromocytoma. Cellular and Molecular Neurobiology, Springer Verlag, 2010. hal-01706432 HAL Id: hal-01706432 https://hal-normandie-univ.archives-ouvertes.fr/hal-01706432 Submitted on 20 Jul 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Expression of Trophic Peptides and Their Receptors in Chromaffin Cells and Pheochromocytoma Erwan Thou/nnon • Alice Pierre • Laurent Yon • Youssef Anouar Abstract Pheochromocytomas are catecholamine-pro- Introduction ducing tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal location. Along with catechola- Pheochromocytomas are neuroendocrine tumors arising mines, tumoral cells produce and secrete elevated quanti- from chromaffin cells of the adrenal medulla or extra- ties of trophic peptides which are normally released in a adrenal locations. These tumors exhibit impaired control of regulated manner by the normal adrenal medulla. Among peptide and hormone biosynthesis and secretion, resulting these peptides, the amounts of pituitary adenylate cyclase- in an exacerbated production of these factors (Thoue¨nnon activating polypeptide (PACAP), adrenomedullin (AM), et al. 2007). In particular, the main clinical symptoms and neuropeptide Y (NPY) are particularly high. These indicating the occurrence of a pheochromocytoma are peptides can exert endocrine, paracrine or autocrine effects provoked by excessive release of catecholamines, dopa- in numerous cell types. In particular, they have been shown mine, norepinephrine, and epinephrine, into the blood- to be involved in cell proliferation and survival, catechol- stream. Along with catecholamines, pheochromocytomas amine production and secretion, and angiogenesis. Some produce and secrete numerous peptides. These peptides are of these processes are exacerbated in pheochromocy- also secreted along with catecholamines in physiological tomas, raising the possibility of the involvement of trophic conditions, in order to participate in homeostatic regula- peptides. Here, we review the expression levels of NPY, tions. Thus, peptides, such as neuropeptide Y (NPY) and PACAP, and AM and theirs receptors in chromaffin cells adrenomedullin (AM), play an important role in the stress and pheochromocytomas, and address their possible response (Edvinsson et al. 1983; Shimosawa and Fujita implication in the adrenal medulla tumorigenesis and 2005). Other peptides, such as pituitary adenylate cyclase- malignant development of pheochromocytomas. activating polypeptide (PACAP) can act as neurotrans- mitters in chromaffin cells (Lamouche and Yamaguchi Keywords Chromaffin cells Á Pheochromocytomas Á 2003; Payet et al. 2003). In addition, these peptides can Trophic peptides Á Tumorigenesis Á Malignancy also act locally as trophic factors. In particular, NPY, AM, and PACAP have been shown to be involved in hormone production and secretion, as well as proliferation, survival or differentiation of numerous cell types (Shimosawa and Fujita 2005; Dumont and Quirion 2006; Vaudry et al. E. Thou/nnon Á A. Pierre Á L. Yon Á Y. Anouar (&) 2009). In pathophysiological conditions, alteration of NPY, INSERM, U982, DC2N, IFRMP23, University of Rouen, AM, and PACAP expression, production and regulated Mont-Saint-Aignan, France e-mail: [email protected] secretion may lead to potential paracrine, autocrine or endocrine defects. Although these peptides have been Present Address: extensively studied in different tumors, such as brain / E. Thou nnon tumors, breast carcinomas, prostate cancer, and neurobl- Section on Cellular Neurobiology, Laboratory of Developmental Neurobiology, Eunice Kennedy Shriver NICHD, NIH, astomas, their roles in pheochromocytomas, where they are Bethesda, MD 20892, USA present in very high quantities, remain poorly understood (Garcia-Fernandez et al. 2004; Moretti et al. 2006; accordance with the chemokines receptor nomenclature Nakamura et al. 2006; Ruscica et al. 2007). (Bleul et al. 1996). In this review, we focused on the expression of NPY, In the human adrenal medulla, the receptors Y1, Y2, Y4, PACAP, and AM and their receptors in adrenal medulla, and Y5 are expressed and functional, indicating that NPY and benign and malignant pheochromocytomas. We also exerts autocrine effects in this tissue (Cavadas et al. 2001; described their effects on chromaffin cells and pheochro- Korner et al. 2004; Spinazzi et al. 2005). The expression of mocytes, and how they could possibly be involved in the CXCR4 in this tissue has not been shown. adrenal gland tumorigenesis and pheochromocytoma Few studies have reported on the effect of NPY on metastasis. chromaffin cells. In human and murine chromaffin cells in primary culture, NPY is able to stimulate catecholamine secretion (Cavadas et al. 2001, 2006). It has also been shown NPY that NPY treatment of rat or bovine chromaffin cells in primary culture is able to inhibit cholinergic agonist-induced NPY is a 36-amino acid peptide originally isolated from catecholamine secretion (Hexum and Russett 1989; Shi- porcine brain (Tatemoto et al. 1982). This neuropeptide moda et al. 1993). Strikingly, the opposite effect has been acts as a co-transmitter, a neuromodulator and a neuro- observed when the adrenal gland was perfused (Hexum and hormone, and plays an important role in numerous physi- Russett 1989). In addition to its role in the regulation of ological processes such as food intake, hormone secretion catecholamine secretion, NPY is also able to act upstream, at or regulation of the immune system (Zukowska et al. the level of catecholamine biosynthesis, as shown by tyro- 2003). NPY is also considered as a growth factor for sev- sine hydroxylase (TH) overexpression observed in rat eral cell types such as neuronal cells or smooth muscle adrenal medulla in which NPY has been injected (Hong et al. cells (Hansel et al. 2001; Pons et al. 2003). NPY is an 1995). Moreover, a simultaneous treatment by ATP and angiogenic factor able to stimulate the proliferation and NPY enhanced TH serine 31-phosphorylation, which would migration of endothelial cells, the formation of capillary stabilize this enzyme (Luke and Hexum 2008). tubes and the revascularization of ischemic tissues (Lee In human pheochromocytomas, the existence of et al. 2003). Moreover, NPY has already been shown to be NPY-producing cells and high NPY concentrations have involved in cell proliferation, angiogenesis, invasion, and been reported (deS Senanayake et al. 1995). These high metastasization of endocrine-related tumors (Ruscica et al. intra-tumoral quantities of NPY can be explained by a 2007). strong expression of the gene, associated with an efficient In human and other mammalian species, high concen- maturation of the precursor (O’Hare and Schwartz 1989; trations of NPY have been found in the brain and the Thoue¨nnon et al. 2010). In pheochromocytoma patients, sympathetic nerve system, including adrenal medulla plasma NPY concentration is often elevated, particularly (Allen et al. 1983). In the latter tissue, NPY concentrations when the tumor is malignant. However, the percentage of are higher than those measured in the adrenal cortex in all patients with elevated plasma NPY levels is similar for studied species (Allen et al. 1983; de Quidt and Emson benign and malignant tumors (Grouzmann et al. 1990). In 1986). tumoral tissue, NPY expression has been shown to be NPY is co-secreted with norepinephrine and exerts a lower in malignant compared to benign pheochromocyto- strong vasoconstrictor effect on cardiovascular system mas (Thoue¨nnon et al. 2010), although the differences were vessels, making this peptide an actor of the stress response not found statistically significant in another study who also (Edvinsson et al. 1983). compared the two tumor subtypes (deS Senanayake et al. So far, six receptors, Y1, Y2, Y3, Y4, Y5, and y6, have 1995; Thoue¨nnon et al. 2010). In a subtype of hereditary been described as NPY receptors. In human, the y6 pheochromocytomas associated with mutation of the von receptor is a pseudogene, coding for a non-functional Hippel–Lindau gene, it has been shown that the expression truncated protein (Rose et al. 1997). Moreover, there is level of NPY was significantly lower than in other hered- some confusion regarding the human Y3 receptor, fre- itary and sporadic pheochromocytomas (Cleary et al. quently described as a putative and uncharacterized 2007). Together, these observations suggest that NPY receptor (Fetissov et al. 2004; Larhammar and Salaneck levels are high but variable in pheochromocytoma and that 2004). However, a recent update of the National Center for this peptide could be differentially produced by different Biotechnology Information (NCBI) website clarified the tumor subtypes. situation: the Y3 receptor
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