The Role of the ACTH Receptor in Adrenal Tumors: Identification of a Novel Microsatellite Marker

Abstract

In vitro, the growth inhibiting effect of ACTH on adrenocortical cells is well documented, even though there are reports of opposite effects under defined cell culture conditions. In vivo, activation of the ACTH receptor (ACTHR) has a trophic effect on the adrenal cortex, while the effects on proliferation are still under discussion, especially since other POMC derived peptides have been characterized. However, ACTH is thought to act as a differentiation factor with inhibiting effects on tumor growth. In undifferentiated adrenocortical carcinomas, ACTHR expression is frequently lost, which is associated with extensive tumor growth. We describe a new microsatellite marker within the intron of the ACTHR gene termed ACTHRint1. In a series of 114 patients with various adrenal and non-adrenal tumors, the rate of heterozygosity was 100 %. Only one out of 57 patients with adrenocortical adenoma showed LOH at the ACTHR locus, whereas 4 of 10 carcinomas had loss of one allele. Patients suffering from tumors with LOH showed a more aggressive disease course and had earlier recurrences with poor prognosis. These data confirm earlier findings that adrenocortical carcinomas frequently show loss of ACTHR expression, which is associated with a more aggressive tumor growth. However, whether the ACTHR is directly involved in tumor growth or acts a marker of differentiation that is lost in more advanced tumor stages is still not clear.

ACTH - Corticotropin - ACTH receptor - Corticotropin receptor - MC2R - Adrenal tumor - Adrenal carcinoma - ACTHRint1 - LOH

References

• 1 Mountjoy K G, Robbins L S, Mortrud M T, Cone R D. The cloning of a family of genes that encode the melanocortin receptors.  Science. 1992;  257 1248-1251
• 2 Lotfi C F, Todorovic Z, Armelin H A, Schimmer B P. Unmasking a growth-promoting effect of the adrenocorticotropic hormone in Y1 mouse adrenocortical tumor cells.  J Biol Chem. 1997;  272 29 886-29 891
• 3 Gallo-Payet N, Payet M D. Mechanism of action of ACTH: beyond cAMP.  Microsc Res Tech. 2003;  61 275-287
• 4 Mountjoy K G, Bird I M, Rainey W E, Cone R D. ACTH induces up-regulation of ACTH receptor mRNA in mouse and human adrenocortical cell lines.  Mol Cell Endocrinol. 1994;  99 R17-20
• 5 Clark A J, Weber A. Adrenocorticotropin insensitivity syndromes.  Endocr Rev. 1998;  19 828-843
• 6 Cater D B, Stack-Dunne M P. The histological changes in the adrenal of the hypophysectomised rat after treatment with pituitary preparations.  J Pathol Bacteriol. 1953;  66 119-133
• 7 Mazzocchi G, Malendowicz L K, Rebuffat P, Robba C, Gottardo G, Nussdorfer G G. Short- and long-term effects of ACTH on the adrenal zona glomerulosa of the rat. A coupled stereological and enzymological study.  Cell Tissue Res. 1986;  243 303-310
• 8 Masui H, Garren L D. Inhibition of replication in functional mouse adrenal tumor cells by adrenocorticotropic hormone mediated by adenosine 3’:5’-cyclic monophosphate.  Proc Natl Acad Sci U S A. 1971;  68 3206-3210
• 9 Weidman R E, Gill G N. Differential effects of ACTH or 8-Dr-cAMP on growth and replicationin a functional adrenal tumor cell line.  J Cell Physiol. 1977;  90 91-103
• 10 Morera A M, Saez J M. In vitro mitogenic and steroidogenic effects of ACTH analogues on an adrenal tumor cell line (Y-1).  Exp Cell Res. 1980;  127 446-451
• 11 Ramachandran J, Suyama A T. Inhibition of replication of normal adrenocortical cells in culture by adrenocorticotropin.  Proc Natl Acad Sci USA. 1975;  72 113-117
• 12 Gospodarowicz D, Handley H H. Stimulation of division of Y1 adrenal cells by a growth factor isolated from bovine pituitary glands.  Endocrinology. 1975;  97 102-107
• 13 Hornsby P J, Gill G N. Hormonal control of adrenocortical cell proliferation. Desensitization to ACTH and interaction between ACTH and fibroblast growth factor in bovine adrenocortical cell cultures.  J Clin Invest. 1977;  60 342-352
• 14 Simonian M H, Gill G N. Regulation of the fetal human adrenal cortex: effects of adrenocorticotropin on growth and function of monolayer cultures of fetal and definitive zone cells.  Endocrinology. 1981;  108 1769-1779
• 15 Armato U, Andreis P G, Draghi E, Meneghelli V. Primary tissue culture of normal adult human decapsulated adrenal cortex: radioautographic studies on the metabolic effects of ACTH1 - 24.  Horm Res. 1975;  6 105-115
• 16 Armato U, Nussdorfer G G, Neri G, Draghi E, Andreis P G, Mazzocchi G, Mantero F. Effects of ACTH and 3’,5’-cyclic purine nucleotides on the morphology and metabolism of normal adult human adrenocortical cells in primary tissue culture.  Cell Tissue Res. 1978;  190 187-205
• 17 Menapace L, Armato U, Whitfield J F. The effects of corticotrophin (ACTH1 - 24), cyclic AMP and TPA (12-O-tetradecanoyl phorbol-13-acetate) on DNA replication and proliferation of primary rabbit adrenocortical cells in a synthetic medium.  Biochem Biophys Res Commun. 1987;  148 1295-1303
• 18 Arola J, Heikkila P, Kahri A I. Biphasic effect of ACTH on growth of rat adrenocortical cells in primary culture.  Cell Tissue Res. 1993;  271 169-176
• 19 Armato U, Nussdorfer G G, Andreis P G, Mazzochi G, Draghi E. Primary tissue culture of human adult adrencortical cells. Methodology and electron microscopic observations on ACTH-deprived and ACTH-treated cortical cells.  Cell Tissue Res. 1974;  155 155-180
• 20 Masui H, Garren L D. On the mechanism of action of adrenocorticotropic hormone. Stimulation of deoxyribonucleic acid polymerase and thymidine kinase activities in adrenal glands.  J Biol Chem. 1970;  245 2627-2632
• 21 Masui H, Garren L D. On the mechanism of action of adrenocorticotropic hormone. The stimulation of thymidine kinase activity with altered properties and changed subcellular distribution.  J Biol Chem. 1971;  246 5407-5413
• 22 Payet N, Lehoux J G, Isler H. Effect of ACTH on the proliferative and secretory activities of the adrenal glomerulosa.  Acta Endocrinol (Copenh). 1980;  93 365-374
• 23 Dallman M F, Engeland W C, Holzwarth M A, Scholz P M. Adrenocorticotropin inhibits compensatory adrenal growth after unilateral adrenalectomy.  Endocrinology. 1980;  107 1397-1404
• 24 Dallman M F. Control of adrenocortical growth in vivo.  Endocr Res. 1984;  10 213-242
• 25 Lowry P J, Silas L, McLean C, Linton E A, Estivariz F E. Pro-gamma-melanocyte-stimulating hormone cleavage in adrenal gland undergoing compensatory growth.  Nature. 1983;  306 70-73
• 26 Estivariz F E, Iturriza F, McLean C, Hope J, Lowry P J. Stimulation of adrenal mitogenesis by N-terminal proopiocortin peptides.  Nature. 1982;  297 419-422
• 27 Estivariz F E, Carino M, Lowry P J, Jackson S. Further evidence that N-terminal pro-opiomelanocortin peptides are involved in adrenal mitogenesis.  J Endocrinol. 1988;  116 201-206
• 28 Bicknell A B, Lomthaisong K, Woods R J, Hutchinson E G, Bennett H P, Gladwell R T, Lowry P J. Characterization of a serine protease that cleaves pro-gamma-melanotropin at the adrenal to stimulate growth.  Cell. 2001;  105 903-912
• 29 Fassnacht M, Hahner S, Hansen I A, Kreutzberger T, Zink M, Adermann K, Jakob F, Troppmair J, Allolio B. N-terminal proopiomelanocortin acts as a mitogen in adrenocortical tumor cells and decreases adrenal steroidogenesis.  J Clin Endocrinol Metab. 2003;  88 2171-2179
• 30 Coll A P, Challis B G, Thresher R, Yeo G, Tierney T, Halsall D, O’Rahilly S. ACTH treatment restores normal adrenal cortical architecture in corticosterone deficient POMC knockout mice.  Oral presentation at the endocrine society 85th annual meeting, Philadelphia. 2003;  OR 37-34
• 31 Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos G P, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis.  J Clin Endocrinol Metab. 1997;  82 3054-3058
• 32 Naville D, Jaillard C, Barjhoux L, Durand P, Begeot M. Genomic structure and promoter characterization of the human ACTH receptor gene.  Biochem Biophys Res Commun. 1997;  230 7-12
• 33 Reincke M, Beuschlein F, Latronico A C, Arlt W, Chrousos G P, Allolio B. Expression of adrenocorticotrophic hormone receptor mRNA in human adrenocortical neoplasms: correlation with P450scc expression.  Clin Endocrinol (Oxf). 1997;  46 619-626
• 34 Reincke M, Beuschlein F, Menig G, Hofmockel G, Arlt W, Lehmann R, Karl M, Allolio B. Localization and expression of adrenocorticotropic hormone receptor mRNA in normal and neoplastic human adrenal cortex.  J Endocrinol. 1998;  156 415-423