Role of the Insulin-like Growth Factor System in Adrenocortical Growth Control and Carcinogenesis

 

 Buy Article Permissions and Reprints

Abstract

Clinically silent adrenocortical adenomas are the most frequent abnormalities in the adrenal gland. In contrast, adrenocortical carcinoma is a rare tumor with an extremely poor prognosis. The factors responsible for the frequent occurrence of benign adrenocortical tumors on one hand and the rare malignant transformation on the other are not known. Several genetic alterations such as loss of imprinting or loss of heterozygosity of the 11p15 gene locus causing a strong IGF-II overexpression have been demonstrated in the majority of adrenocortical carcinomas. In addition to IGF-II overexpression, increased levels of the IGF-I-receptor and IGFBP-2 have been found in advanced human adrenocortical carcinomas, suggesting an important role for the IGF-system in adrenocortical carcinogenesis. IGFs are potent mitogens regulating growth and apoptosis through interaction with the IGF-I-receptor, and overexpression of the human IGF-I-receptor promotes ligand-dependent neoplastic transformation in a variety of different cell systems. It is evident, therefore, that high levels of IGF-II in combination with overexpression of the IGF-I-receptor can provide a significant growth advantage for adrenocortical carcinoma cells and thus contribute to the highly malignant phenotype of this rare type of cancer. Additionally, it has been shown that overexpression of IGFBP-2 can promote malignant transformation of Y1 mouse adrenocortical tumor cells through unknown IGF-independent mechanisms. As one possible mechanism, we have recently found altered expression of catalase in IGFBP-2-overexpressing tumor cells, thus implicating IGFBP-2 in influencing intracellular peroxide levels. However, since transgenic mice with IGF-II or IGFBP-2 overexpression in the adrenal gland do not show an increased frequency of adrenal tumors, IGF-II or IGFBP-2 may act as progression factors but not as initiation factors in adrenocortical tumorigenesis.

References

• 1 Reincke M. Mutations in adrenocortical tumors.  Horm Met Res. 1998;  30 447-455
  PubMedGoogle Scholar
• 2 Kjellmann M, Larsson C, Bäckdähl M. Genetic background of adrenocortical tumor development.  World J Surg. 2001;  25 948-95
  CrossrefPubMedGoogle Scholar
• 3 Weber M M, Kiess W, Beikler T, Simmler P, Reichel M, Adelmann B, Kessler U, Engelhardt D. Identification and characterization of insulin-like growth factor I (IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in bovine adrenal cells.  Eur J Endocrinol. 1994;  130 265-270
  PubMedGoogle Scholar
• 4 Weber M M, Simmler P, Fottner C, Engelhardt D. Insulin-like growth factor II (IGF-II) is more potent than IGF-I in stimulating cortisol secretion from cultured bovine adrenocortical cells: Interaction with the IGF-I-receptor and IGF-binding proteins.  Endocrinology. 1995;  136 3714-3720
  CrossrefPubMedGoogle Scholar
• 5 Weber M M, Fottner C, Engelhardt D. Adrenocortical and adrenomedullary cells. In: Bidley S (ed) Endocrine cell culture. Cambridge University Press 1998: 16-31
  Google Scholar
• 6 Fottner C, Engelhardt D, Weber M M. Regulation of steroidogenesis by insulin-like growth factors (IGFs) in adult human adrenocortical cells: IGF-I and, more potently, IGF-II preferentially enhance androgen biosynthesis through interaction with the IGF-I-receptor and IGF-binding proteins.  J Endocrinol. 1998;  158 409-417
  CrossrefPubMedGoogle Scholar
• 7 Fottner C, Engelhardt D, Weber M M. Characterization of Insulin-like growth factor binding proteins (IGFBPs) secreted by bovine adrenocortical cells in primary culture: Regulation by Insulin-like growth factors (IGFs) and adrenocorticotropin (ACTH).  Hormone and Metabolism Research. 1999;  31 203-208
  PubMedGoogle Scholar
• 8 Fottner C, Elmlinger M, Engelhardt D, Weber M M. Identification and characterization of Insulin-like growth factor (IGF) binding protein-expression and -secretion by adult human adrenocortical cells: Differential regulation by IGFs and adrenocorticotropin.  Journal of Endocrinology. 2001;  168 465-474
  CrossrefPubMedGoogle Scholar
• 9 Penhoat A, Rainey W E, Viard I, Saez J M. Regulation of adrenal cell-differentiated functions by growth factors.  Horm Res. 1994;  42 39-43
  PubMedGoogle Scholar
• 10 Mesiano S, Mellon S H, Jaffe R B. Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland.  J Clin Endocrinol Metab. 1993;  76 968-976
  CrossrefPubMedGoogle Scholar
• 11 Voutilainen R, Miller W L. Developmental and hormonal regulation of mRNAs for insulin-like growth factor II and steroidogenic enzymes in human fetal adrenals and gonads.  DNA. 1988;  7 9-15
  PubMedGoogle Scholar
• 12 Ilvesmäki V, Blum W F, Voutilainen R. Insulin-like growth factor-II in human fetal adrenals: regulation by ACTH, protein kinase C and growth factors.  J Endocrinol. 1992;  137 533-42
  PubMedGoogle Scholar
• 13 Ilvesmäki V, Kahri A I, Miettinen P J, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas.  J Clin Endocrinol Metab. 1993;  77 852-858
  CrossrefPubMedGoogle Scholar
• 14 Hesse V, Jahreis G, Schambach H, Vogel H, Vilser C, Seewald H, Börner A, Deichl A. Insulin-like growth factor I correlations to changes of the hormonal status in puberty and age.  Exp Clin Endocrinol. 1994;  102 289-298
  PubMedGoogle Scholar
• 15 Glasscock G F, Hein A N, Millar J A, Hintz R L, Rosenfeld R G. Effects of continuous infusion of insulin-like growth factor I and II, alone and in combination with thyroxine or growth hormone, on the neonatal hypophysectomized rat.  Endocrinology. 1992;  130 203-210
  CrossrefPubMedGoogle Scholar
• 16 Rogler C E, Yang D, Rossetti L, Donohoe J, Alt E, Chang C E, Rosenfeld R, Neely K, Hintz R. Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice.  J Biol Chem. 1994;  260 3779-13 784
  PubMedGoogle Scholar
• 17 Ward A, Bates P, Fisher R, Richardson L, Graham C F. Disproportionate growth in mice with IGF-II transgenes.  Proc Natl Acad Sci USA. 1994;  91 10 365-10 369
  PubMedGoogle Scholar
• 18 Wilson D M, Thomas J A, Hamm T E, Wyche J, Hintz R L, Rosenfeld R G. Transplantation of IGF-II secreting tumours into nude rodents.  Endocrinology. 1987;  120 1896-1901
  PubMedGoogle Scholar
• 19 Rainey W E, Parker C R, Rehmann K, Carr B R. The adrenal genetic puzzle: how do fetal and adult pieces differ?.  Endocr Res. 2002;  28 611-622
  CrossrefPubMedGoogle Scholar
• 20 Mesiano S, Jaffe R B. Developmental and functional biology of the primate fetal adrenal cortex.  Endocr Rev. 1997;  18 378-403
  CrossrefPubMedGoogle Scholar
• 21 Han V K, Lu F, Bassett N, Yang K P, Delhanty P J, Challis J R. Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II.  Endocrinology. 1992;  131 3100-3109
  CrossrefPubMedGoogle Scholar
• 22 Voutilainen R, Miller W L. Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain-cleavage enzyme, P450ssc, in human steroidogenic tissues.  Proc Natl Acad Sci USA. 1987;  84 1590-1594
  PubMedGoogle Scholar
• 23 l' Allemand D, Penhoat A, Blum W, Saez J M. Is there a local IGF-system in human adrenocortical cells?.  Mol Cell Endocrinol. 1998;  140 169-73
  CrossrefPubMedGoogle Scholar
• 24 Weber M M, Kiess W, Beikler T, Simmler P, Reichel M, Adelmann B, Kessler U, Engelhardt D. Identification and characterization of insulin-like growth factor I (IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in adrenal cells.  Eur J Endocrinol. 1994;  130 265-270
  PubMedGoogle Scholar
• 25 Penhoat A, Rainey W E, Viard I, Saez J M. Regulation of adrenal cell-differentiated functions by growth factors.  Hormone Research. 1994;  42 39-43
  PubMedGoogle Scholar
• 26 Weber M M, Auernhammer C J, Kiess W, Engelhardt D. Insulin-like growth factor receptors in normal and tumorous adult human adrenocortical glands.  Eur J Endocrinol. 1997;  136 296-303
  CrossrefPubMedGoogle Scholar
• 27 Kamio T, Shigematsu K, Kawai K, Tsuchiyama H. Immunoreactivity and receptor expression of Insulin-like growth factor I and insulin in human adrenal tumors.  Am J Pathol. 1991;  138 83-91
  PubMedGoogle Scholar
• 28 Logié A, Boulle N, Gaston V, Perin L, Bourdou P, Le Bouc Y. Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line.  J Mol Endocrinol. 1999;  23 23-32
  CrossrefPubMedGoogle Scholar
• 29 LeRoith D, Roberts C T. The Insulin-like growth factor system and cancer.  Cancer letters. 2003;  195 127-137
  CrossrefPubMedGoogle Scholar
• 30 Grimberg A, Cohen P. Role of Insulin-like growth factors and their binding proteins in growth control and carcinogenesis.  J Cell Physiol. 2000;  183 1-9
  CrossrefPubMedGoogle Scholar
• 31 Ilvesmäki V, Blum W F, Voutilainen R. Insulin-like growth factor binding proteins in the human adrenal gland.  Mol Cell Endocrinol. 1992;  97 71-79
  PubMedGoogle Scholar
• 32 Fottner C, Spöttl G, Engelhardt D, Weber M M. The divergent effect of insulin-like growth factor binding protein (IGFBP)-1 on the steroidogenic effect of IGF-I and IGF-II in bovine adrenocortical cells is not due to its phosphorylation status.  Growth Hormone and IGF-Research. 2003;  13 219
  PubMedGoogle Scholar
• 33 Weber M M, Fottner C, Wolf E. The role of the insulin-like growth factor (IGF) system in adrenocortical tumorigenesis.  Eur J Clin Invest. 2000;  30 69-75
  CrossrefPubMedGoogle Scholar
• 34 Conlon M A, Tomas F M, Owens P, Wallace J C, Howarth G S, Ballard F J. Long R3 Insulin-like growth factor-I (IGF-I) infusion stimulates organ growth but reduces plasma IGF-I, IGF-II and IGF binding protein concentrations in the guinea pig.  J Endocrinol. 1995;  146 247-253
  PubMedGoogle Scholar
• 35 Hoeflich A, Weber M M, Fisch T, Nedbal S, Fottner C, Elmlinger M W, Wanke R, Wolf E. Insulin-Like Growth Factor-Binding Protein-2 (IGFBP-2) separates hypertrophic and hyperplastic effects of Growth Hormone (GH)/IGF-I excess on adrenocortical cells in vivo.  FASEB-J. 2002;  16 1721-1731
  PubMedGoogle Scholar
• 36 Edgren M, Eriksson B, Wilander E, Westlin J E, Nilsson S, Öberg K. Biological characteristics of adrenocortical carcinoma: a study of p53, IGF, EGF-r, Ki-67 and PCNA in 17 adrenocortical carcinomas.  Anticancer Res. 1997;  17 1303-1310
  PubMedGoogle Scholar
• 37 de Fraipont F D, Le Moigne G, Defaye G, El Atifi M, Berger F, Houlgatte R, Gicquel C, Plouin P F, Bertagna X, Chabre O, Feige J J. Transcription profiling of benign and malignant adrenal tumors by cDNA macro-array analysis.  Endocr Res. 2002;  28 785-786
  CrossrefPubMedGoogle Scholar
• 38 Schneid H, Seurin D, Noguiez P, Le Bouc Y. Abnormalities of insulin-like growth factor (IGF-I and IGF-II) genes in human tumor tissue.  Growth Regulation. 1992;  2 45-54
  PubMedGoogle Scholar
• 39 Gicquel C, Bertagna X, Le Bouc Y. Recent advances in the pathogenesis of adrenocortical tumours.  Eur J Endocrinol. 1995;  133 133-144
  CrossrefPubMedGoogle Scholar
• 40 Faical S, Maciel R MB, Nose-Alberti V, Santos M C, Kater C E. Immunodetection of Insulin-like growth factor I (IGF-I) in normal and pathological adrenocortical tissue.  Endocrine Pathology. 1998;  9 63-70
  PubMedGoogle Scholar
• 41 Ilvesmaki V, Kahri A I, Miettinen P J, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas.  J Clin Endocrinol Metab. 1993;  77 852-858
  CrossrefPubMedGoogle Scholar
• 42 Giordano T J, Thomas D G, Kuick R, Lizyness M, Misek D E, Smith A L, Sanders D, Aljundi R T, Gauger P G, Thompson N W, Taylor J MG, Hanash S. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis.  Am J Pathol. 2003;  162 521-531
  CrossrefPubMedGoogle Scholar
• 43 Erickson L A, Jin L, Sebo T J, Lohse C, Pankratz V S, Kendrick M L, van Heerden J A, Thompson G B, Gran C S, Lloyd R V. Pathological features and expression of Insulin-like growth factor-2 in adrenocortical neoplasms.  Endocr Pathol. 2001;  12 429-435
  CrossrefPubMedGoogle Scholar
• 44 Boulle N, Logié A, Gicquel C, Perin L, Le Bouc Y. Increased levels of Insulin-like growth factor II (IGF-II) and IGF-Binding Protein-2 are associated with malignancy in sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 1998;  83 1713-1720
  CrossrefPubMedGoogle Scholar
• 45 Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos J M, Schlumberger M, Plouin P F, Luton J P, Le Bouc Y. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors.  Cancer Res. 2001;  61 6762-6767
  PubMedGoogle Scholar
• 46 Yano T, Linehan M, Anglard P. Genetic changes in human adrenocortical carcinomas.  J Natl Cancer Inst. 1989;  81 518-523
  PubMedGoogle Scholar
• 47 Le Bouc Y, Noguiez P, Sondermeijer P, Dreyer D, Girard F, Binoux M. A new 5′-non-coding region for human placental IGF-II mRNA expression.  FEBS Lett. 1987;  222 181-185
  CrossrefPubMedGoogle Scholar
• 48 Wolf E, Kramer R, Blum W F, Föll J, Brem G. Consequences of postnatally elevated insulin-like growth factor-II in transgenic mice: endocrine changes and effects on body and organ growth.  Endocrinology. 1994;  135 1877-1886
  CrossrefPubMedGoogle Scholar
• 49 Weber M M, Fottner C, Schmidt P, Brodowski K MH, Gittner K, Lahm H, Engelhardt D, Wolf E. Postnatal overexpression of IGF-II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis.  Endocrinology. 1999;  140 1537-1543
  CrossrefPubMedGoogle Scholar
• 50 Wolf E, Hoeflich A, Lahm H. What is the function of IGF-II in postnatal life? Answers from transgenic mouse models.  Growth Horm IGF Res. 1998;  8 185-193
  PubMedGoogle Scholar
• 51 Kirschner L S. Signaling pathways in adrenocortical cancer.  Ann N Y Acad Sci. 2002;  58 222-239
  PubMedGoogle Scholar
• 52 Toretsky J A, Helman L J. Involvement of IGF-II in human cancer.  J Endocrinol. 1996;  149 367-372
  CrossrefPubMedGoogle Scholar
• 53 Wilkin F, Gagné N, Paquette J, Oligny L L, Deal C. Pediatric adrenocortical tumors: molecular events leading to Insulin-like growth factor II gene overexpression.  J Clin Endocrinol Metab. 2000;  85 2048-2056
  CrossrefPubMedGoogle Scholar
• 54 Gicquel C, Bertagna X, Schneid H, Francillard-Leblond M, Luton J P, Girard F. et al . Rearrangements at the 11p15 locus and over expression of insulin-like growth factor-II gene in sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 1994;  78 1444-53
  CrossrefPubMedGoogle Scholar
• 55 Gicquel C, Raffin-Sanson M L, Gaston V, Bertagna X, Plouin P F, Schlumberger M, Louvel A, Luton J P, Le Bouc Y. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: Study on a series of 82 tumors.  J Clin Endocrinol Metab. 1997;  82 2559-2565
  CrossrefPubMedGoogle Scholar
• 56 Liu J, Kahri A I, Heikkilä P, Ilvesmäki V, Voutilainen R. H19 and insulin-like growth factor-II gene expression in adrenal tumors and cultured adrenal cells.  J Clin Endocrinol Metab. 1995;  80 492-496
  CrossrefPubMedGoogle Scholar
• 57 Bourcigaux N, Gaston V, Logie A, Bertagna X, Le Bouc Y, Gicquel C. High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors.  J Clin Endocrinol Metab. 2000;  85 322-330
  CrossrefPubMedGoogle Scholar
• 58 Schneid H, Seurin D, Vasquez M-P, Gourmelen M, Cabrol S, Le Bouc Y. Parental allele specific methylation of the human insulin-like growth factor-II gene and Beckwith Wiedemann syndrome.  J Med Genet. 1993;  30 353-362
  PubMedGoogle Scholar
• 59 Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C. The INS 59 variable number of tandem repeats is associated with IGF2 expression in humans.  J Biol Chem. 1998;  273 14 158-14 164
  PubMedGoogle Scholar
• 60 Yano T, Linehan M, Anglard P, Lerman M I, Daniel L N, Stein C A. Genetic changes in human adrenocortical carcinomas.  J Natl Cancer Inst. 1989;  81 518-523
  PubMedGoogle Scholar
• 61 Thibout H, Martinerie C, Créminon C, Godeau F, Boudou P, Le Bouc Y, Laurent M. Characterization of Human NOV in Biological Fluids: An Enzyme Immunoassay for the Quantification of Human NOV in Sera from Patients with Diseases of the Adrenal Gland and of the Nervous System.  J Clin Endocrinol Metab. 2003;  88 327-336
  CrossrefPubMedGoogle Scholar
• 62 Martinerie C, Gicquel C, Louvel A, Laurent M, Schofield P N, Le Bouc Y. Altered Expression of novH Is Associated with Human Adrenocortical Tumorigenesis.  J Clin Endocrinol Metab. 2001;  86 3929-3940
  CrossrefPubMedGoogle Scholar
• 63 Weber M M, Fottner C, Liu S B, Jung M C, Engelhardt D, Baretton G B. Overexpression of the insulin-like growth factor I receptor in human colon carcinomas.  Cancer. 2002;  95 2086-2095
  CrossrefPubMedGoogle Scholar
• 64 Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even P C, Cervera P, Le Bouc Y. IGF-I-receptor regulates lifespan and rsistance to oxidative stress in mice.  Nature. 2003;  421 182-187
  CrossrefPubMedGoogle Scholar
• 65 Lithgow G, Gill M S. Cost-free longevity in mice?.  Nature. 2003;  421 125-127
  CrossrefPubMedGoogle Scholar
• 66 Rubin R, Baserga R. Insulin-like growth factor-I receptor. Its role in cell proliferation, apoptosis, and tumorigenicity.  Lab Invest. 1995;  73 311-331
  PubMedGoogle Scholar
• 67 Werner H, Shalita-Chesner M, Abramovitch S, Idelman G, Shaharabani-Gargir L, Glaser T. Regulation of the insulin-like growth factor-I receptor gene by oncogenes and antioncogenes: implications in human cancer.  Mol Genet Metab. 2000;  71 315-320
  CrossrefPubMedGoogle Scholar
• 68 Werner H, Le Roith D. New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia.  Cell Mol Life Sci. 2000;  57 932-942
  PubMedGoogle Scholar
• 69 Neuberg M, Buckbinder L, Seizinger B, Kley N. The p53/IGF-1 receptor axis in the regulation of programmed cell death.  Endocrine. 1997;  7 107-109
  PubMedGoogle Scholar
• 70 Makos Wales B, Biel M, El Deiry W. p53 activates expression of HIC-1, a new dandidate tumor suppressor gene on 17p13.3.  Nat Med. 1995;  1 570-582
  PubMedGoogle Scholar
• 71 Werner H, Karnieli E, Rauscher F J, LeRoith D. Wild type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene.  Proc Natl Acad Sci USA. 1996;  93 8318-8323
  CrossrefPubMedGoogle Scholar
• 72 Girnita L, Girnita A, Brodin B. Increased expression of insulin-like growth factor I receptor in malignant cells expressing abberant p53: functional impact.  Cancer Res. 2000;  60 5278-5283
  PubMedGoogle Scholar
• 73 Reincke M, Karl M, Travis W, Mastorakos G, Allolio B, Linehan H, Chrousos G. p53 mutations in human adrenocortical neoplasms: immunhistochemical and molecular studies.  J Clin Endocrinol Metab. 1994;  78 790-796
  CrossrefPubMedGoogle Scholar
• 74 Hoeflich A, Yang Y, Rascher W. et al . Coordinate expression of insulin-like growth factor II (IGF-II) and IGF-II/mannose-6-phosphate receptor mRNA during differentiation of human colon carcinoma cells (caco-2).  Eur J Endocrinol. 1996;  135 49-59
  PubMedGoogle Scholar
• 75 O'Gorman D B, Costello M, Weiss J, Firth S M, Scott C D. Decreased insulin-like growth factor-II/mannose 6-phosphate receptor expression enhances tumorigenicity in JEG-3 cells.  Cancer Res. 1999;  59 5692-5694
  PubMedGoogle Scholar
• 76 Souza R F, Wang S, Thakar M, Smolinski K N, Yin J, Zou T T, Kong D, Abraham J M, Toretsky J A, Meltzer S J. Expression of the wild-type insulin-like growth factor II receptor gene suppresses growth and causes death in colorectal carcinoma cells.  Oncogene. 1999;  18 4063-4068
  CrossrefPubMedGoogle Scholar
• 77 Leboulleux S, Gaston V, Boulle N, Le Bouc Y, Gicquel C. Loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor 2 receptor locus: a frequent but late event in adrenocortical tumorigenesis.  Eur J Endocrinol. 2001;  144 163-168
  CrossrefPubMedGoogle Scholar
• 78 Boulle N, Baudin E, Gicquel C, Logié A, Bertherat J, Penfornis A, Bertagna X, Luton J P, Schlumberger M, Le Bouc Y. Evaluation of plasma insulin-like growth factor binding protein-2 as a marker for adrenocortical tumors.  Eur J Endocrinol. 2001;  144 29-36
  CrossrefPubMedGoogle Scholar
• 79 Hoeflich A, Reisinger E, Lahm H, Kiess W, Blum W F, Kolb H J, Weber M M, Wolf E. Insulin-like growth factor binding protein 2 in tumorigenesis: protector or promoter?.  Cancer Res. 2001;  61 8601-8610
  PubMedGoogle Scholar
• 80 Hoeflich A, Nedbal S, Blum W F, Erhard M, Lahm H, Brehm G, Kolb H J, Wanke R, Wolf E. Growth inhibition in giant growth hormone transgenic mice by overexpression of Insulin-Like Growth Factor-Binding Protein-2 (IGFBP-2).  Endocrinology. 2001;  142 1889-1898
  CrossrefPubMedGoogle Scholar
• 81 Hoeflich A, Fettscher O, Lahm H, Blum W F, Kolb H J, Engelhardt D, Wolf E, Weber M M. Overexpression of insulin-like growth factor-binding protein-2 results in increased tumorigenic potential in Y-1 adrenocortical tumor cells.  Cancer Res. 2000;  60 834-838
  PubMedGoogle Scholar
• 82 Hoeflich A, Fettscher O, Preta G, Lahm H, Kolb H J, Wolf E, Weber M M. Increased Enzyme Activities of Catalase in Tumor Cells Overexpressing IGFBP-2.  Horm Metab Res. 2003;  35 816-821
  Article in Thieme ConnectPubMedGoogle Scholar
• 83 Bernard M H, Sidhu S, Berger N, Peix J L, Marsh D, Robinson B, Gaston V, Le Bouc Y, Gicquel C. A case report in favor of a multistep adrenocortical tumorigenesis.  J Clin Endocrinol Metab. 2003;  88 998-1001
  CrossrefPubMedGoogle Scholar
• 84 Khandwala H M, McCutcheon I E, Flyvbjerg A, Friend K E. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth.  Endocrine Reviews. 2000;  21 215-244
  CrossrefPubMedGoogle Scholar
• 85 Pham-Huu-Trung M T, Villette J M, Bogyo A, Duclos J M, Fiet J, Binoux M. Effects of insulin-like growth factor-I (IGF-I) on enzymatic activity in human adrenocortical cells. Interactions with ACTH.  J Steroid Biochem Molec Biol. 1991;  39 903-909
  PubMedGoogle Scholar
• 86 Naseeruddin S A, Hornsby P J. Regulation of 11β-17α-hydroxylases in cultured bovine adrenocortical cells: 3′,5′-cyclic adenosine monophosphate, insulin-like growth factor-I, and activators of protein kinase C.  Endocrinology. 1990;  127 1673-1681
  PubMedGoogle Scholar
• 87 Penhoat A, Jaillard C, Saez J M. Synergistic effects of corticotropin and insulin-like growth factor I on corticotropin receptors and corticotropin responsiveness in cultured bovine adrenocortical cells.  Biochem Biophys Res Commun. 1989;  165 355-359
  CrossrefPubMedGoogle Scholar
• 88 Pham-Huu-Trung M T, Binoux M. Insulin-like growth factor-I (IGF-I) induces cortisol production in bovine adrenocortical cells in primary culture.  J Steroid Biochem. 1990;  36 583-588
  CrossrefPubMedGoogle Scholar
• 89 Fottner C, Matezki G, Engelhardt D, Weber M M. The divergent effect of insulin-like growth factor binding protein (IGFBP) - 1 on IGF induced cortisol secretion in bovine adrenocortical cells is not due to different affinities of the IGFBP-1-phosphorylation isoforms for IGFs.  Exp Clin Endocrinol & Diabetes. 2001;  109 (Suppl 1) 152
  PubMedGoogle Scholar
• 90 Kristiansen S B, Endoh A, Casson P R, Buster J E, Hornsby P J. Induction of steroidogenic enzyme genes by insulin and IGF-I in cultured adult human adrenocortical cells.  Steroids. 1997;  62 258-265
  CrossrefPubMedGoogle Scholar
• 91 Naaman E, Chatelain P, Saez J M, Durand P. In vitro effect of insulin and insulin-like growth factor-I on cell multiplication and adrenocorticotropin responsiveness of fetal adrenal cells.  Biol Reprod. 1989;  40 570-577
  PubMedGoogle Scholar

Prof. Dr. med. M. M. Weber

Schwerpunkt Endokrinologie und Stoffwechselerkrankungen · I. Medizinische Klinik und Poliklinik · Johannes Gutenberg Universität Mainz

Langenbeckstraße 1 · 55131 Mainz · Germany

Phone: +49 (6131) 177260

Fax: +49 (6131) 175608

Email: MMWeber@uni-mainz.de