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Reviews in Endocrine and Metabolic Disorders

Erschienen in:

01.03.2008

Acromegaly: Re-thinking the cancer risk

verfasst von: Siobhan Loeper, Shereen Ezzat

Erschienen in: Reviews in Endocrine and Metabolic Disorders | Ausgabe 1/2008

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Abstract

Acromegaly is characterized by sustained elevation of circulating growth hormone (GH) and insulin-like growth factor I (IGF-I), and is clearly associated with increased morbidity and overall mortality mainly due to cardiovascular, metabolic, and respiratory diseases. Although cancer-related mortality varies widely amongst retroperspective studies, it appears to be consistently elevated mainly in patients with uncontrolled disease. We review individual tumor types including neoplasms of the colon, breast, prostate, and thyroid where in vitro, animal studies, and studies in non-acromegalic cancer patients have established a role for the GH/IGF-I axis in tumor progression and possibly initiation. We highlight deficiencies in data in acromegalic patients where the evidence is less convincing. Instead, we explore the hypothesis that acromegaly, independent of hormone secretion, is a disease that heralds genetic and/or epigenetic alterations predisposing to cancer risk elsewhere.

Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med 1970;39(153):1–16.PubMed

Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf) 1980;12:71–9.

Nabarro JDN. Acromegaly. Clin Endocrinol (Oxf) 1987;26:481–512.

Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand 1988;223(4):327–35.PubMedCrossRef

Etxabe J, Gaztambide P, Latorre P, Vazquez JA. Acromegaly: an epidemilogical study. J Endocrinol Invest 1993;16:181–7.PubMed

Mustacchi P, Shimkin MB. Occurrence of cancer in acromegaly and in hypopituitarism. Cancer 1957;10(1):100–4.PubMed

Bates AS, Van't Hoff W, Jones JM, Clayton RN. An audit of outcome of treatment in acromegaly. Q J Med 1993;86:293–9.PubMed

Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survivial in acromegaly. Clin Endocrinol (Oxf) 1994;41:95–102.

Swearingen B, Barker FG, Katznelson L, Biller BM, Grinspoon S, Klibanski A, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 1998;83(10):3419–26.PubMed

10.

Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 1998;83(8):2730–4.PubMed

11.

Beauregard C, Truong U, Hardy J, Serri O. Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf) 2003;58(1):86–91.

12.

Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab 2004;89(4):1613–7.PubMed

13.

Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 2004;89(2):667–74.PubMed

14.

Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Niskanen L, Markkanen H, et al. A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 2005;90(7):4081–6.PubMed

15.

Melmed S. Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 2001;86(7):2929–34.PubMed

16.

Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004;25(1):102–52.PubMed

17.

Klein I, Parveen G, Gavaler JS, Vanthiel DH. Colonic polyps in patients with acromegaly. Ann Intern Med 1982;97(1):27–30.PubMed

18.

Brunner JE, Johnson CC, Zafar S, Peterson EL, Brunner JF, Mellinger RC. Colon cancer and polyps in acromegaly: increased risk associated with family history of colon cancer. Clin Endocrinol (Oxf) 1990;32(1):65–71.

19.

Barzilay J, Heatley GJ, Cushing GW. Benign and malignant tumors in patients with acromegaly. Arch Intern Med 1991;151(8):1629–32.PubMed

20.

Ron E, Gridley G, Hrubec Z, Page W, Arora S, Fraumeni JF Jr. Acromegaly and gastrointestinal cancer. Cancer 1991;68(8):1673–7.PubMed

21.

Cheung NW, Boyages SC. Increased incidence of neoplasia in females with acromegaly. Clin Endocrinol (Oxf) 1997;47(3):323–7.

22.

Popovic V, Damjanovic S, Micic D, Nesovic M, Djurovic M, Petakov M, et al. Increased incidence of neoplasia in patients with pituitary adenomas. The Pituitary Study Group. Clin Endocrinol (Oxf) 1998;49(4):441–5.

23.

Higuchi Y, Saeki N, Iuchi T, Uchino Y, Tatsuno I, Uchida D, et al. Incidence of malignant tumors in patients with acromegaly. Endocr J 2000;47(Suppl):S57–60.PubMed

24.

Baris D, Gridley G, Ron E, Weiderpass E, Mellemkjaer L, Ekbom A, et al. Acromegaly and cancer risk: a cohort study in Sweden and Denmark. Cancer Causes Control 2002;13(5):395–400.PubMed

25.

Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary 1999;2(1):29–41.PubMed

26.

Renehan AG, O'Connell J, O'Halloran D, Shanahan F, Potten CS, O'Dwyer ST, et al. Acromegaly and colorectal cancer: a comprehensive review of epidemiology, biological mechanisms, and clinical implications. Horm Metab Res 2003;35(11–12):712–25.PubMed

27.

Delhougne B, Deneux C, Abs R, Chanson P, Fierens H, Laurent-Puig P, et al. The prevalence of colonic polyps in acromegaly: a colonoscopic and pathological study in 103 patients. J Clin Endocrinol Metab 1995;80(11):3223–6.PubMed

28.

Jenkins PJ, Fairclough PD, Richards T, Lowe DG, Monson J, Grossman A, et al. Acromegaly, colonic polyps and carcinoma. Clin Endocrinol (Oxf) 1997;47(1):17–22.

29.

Terzolo M, Reimondo G, Gasperi M, Cozzi R, Pivonello R, Vitale G, et al. Colonoscopic screening and follow-up in patients with acromegaly: a multicenter study in Italy. J Clin Endocrinol Metab 2005;90(1):84–90.PubMed

30.

Renehan AG, Bhaskar P, Painter JE, O'Dwyer ST, Haboubi N, Varma J, et al. The prevalence and characteristics of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 2000;85(9):3417–24.PubMed

31.

Ezzat S, Melmed S. Are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab 1991;72:245–9.PubMed

32.

Melmed S, Casanueva FF, Cavagnini F, Chanson P, Frohman L, Grossman A, et al. Guidelines for acromegaly management. J Clin Endocrinol Metab 2002;87(9):4054–8.PubMed

33.

Ezzat S, Serri O, Chik CL, Johnson MD, Beauregard H, Marcovitz S, et al. Canadian consensus guidelines for the diagnosis and management of acromegaly. Clin Invest Med 2006;29(1):29–39.PubMed

34.

Vasen HF, van Erpecum KJ, Roelfsema F, Raue F, Koppeschaar H, Griffioen G, et al. Increased prevalence of colonic adenomas in patients with acromegaly. Eur J Endocrinol 1994;131(3):235–7.PubMed

35.

Colao A, Balzano A, Ferone D, Panza N, Grande G, Marzullo P, et al. Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly. Clin Endocrinol (Oxf) 1997;47(1):23–8.

36.

Jenkins PJ, Frajese V, Jones AM, Camacho-Hubner C, Lowe DG, Fairclough PD, et al. Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 2000;85(9):3218–21.PubMed

37.

Cats A, Dullaart RP, Kleibeuker JH, Kuipers F, Sluiter WJ, Hardonk MJ, et al. Increased epithelial cell proliferation in the colon of patients with acromegaly. Cancer Res 1996;56(3):523–6.PubMed

38.

Bogazzi F, Russo D, Locci MT, Chifenti B, Ultimieri F, Raggi F, et al. Apoptosis is reduced in the colonic mucosa of patients with acromegaly. Clin Endocrinol (Oxf) 2005;63(6):683–8.

39.

Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clin Endocrinol (Oxf) 2006;64(2):115–21.

40.

Ochsenkuhn T, Bayerdorffer E, Meining A, Schinkel M, Thiede C, Nussler V, et al. Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 1999;85(8):1664–9.PubMed

41.

Veysey MJ, Thomas LA, Mallet AI, Jenkins PJ, Besser GM, Wass JA, et al. Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones. Gut 1999;44(5):675–81.PubMedCrossRef

42.

Lincoln DT, Kaiser HE, Raju GP, Waters MJ. Growth hormone and colorectal carcinoma: localization of receptors. In Vivo 2000;14(1):41–9.PubMed

43.

Thomas MJ. The molecular basis of growth hormone action. Growth Horm IGF Res 1998;8(1):3–11.PubMed

44.

Ross RJ. The GH receptor and GH insensitivity. Growth Horm IGF Res 1999;9(Suppl B):42–5.PubMed

45.

Singh P, Rubin N. Insulinlike growth factors and binding proteins in colon cancer. Gastroenterology 1993;105(4):1218–37.PubMed

46.

Garrouste FL, Remacle-Bonnet MM, Lehmann MM, Marvaldi JL, Pommier GJ. Up-regulation of insulin/insulin-like growth factor-I hybrid receptors during differentiation of HT29-D4 human colonic carcinoma cells. Endocrinology 1997;138(5):2021–32.PubMed

47.

Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z, et al. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 2003;63(22):7708–16.PubMed

48.

Mathews LS, Hammer RE, Behringer RR, D'Ercole AJ, Bell GI, Brinster RL, et al. Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology 1988;123(6):2827–33.PubMed

49.

Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 1989;124(1):40–8.PubMed

50.

Ulshen MH, Dowling RH, Fuller CR, Zimmermann EM, Lund PK. Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone. Gastroenterology 1993;104(4):973–80.PubMed

51.

Ohneda K, Ulshen MH, Fuller CR, D'Ercole AJ, Lund PK. Enhanced growth of small bowel in transgenic mice expressing human insulin-like growth factor I. Gastroenterology 1997;112(2):444–54.PubMed

52.

Lund PK. IGFs and the digestive tract. In: Roberts CT, Rosenfeld RG, editors. The IGF system molecular biology, physiology, and clinical applications. Totowa, NJ: Humana; 1999. p. 517–44.

53.

Yakar S, Pennisi P, Kim CH, Zhao H, Toyoshima Y, Gavrilova O, et al. Studies involving the GH-IGF axis: Lessons from IGF-I and IGF-I receptor gene targeting mouse models. J Endocrinol Invest 2005;28(5 Suppl):19–22.PubMed

54.

Pollak M. Insulin-like growth factor physiology and cancer risk. Eur J Cancer 2000;36(10):1224–8.PubMed

55.

Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363(9418):1346–53.PubMed

56.

Jenkins PJ. Cancers associated with acromegaly. Neuroendocrinology 2006;83(3–4):218–23.PubMed

57.

American Cancer Society. Cancer reference information. Atlanta: American Cancer Society; 2007.

58.

AACE Acromegaly Guidelines Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly. Endocr Pract 2004;10(3):213–25.

59.

Jenkins PJ, Fairclough PD. Screening guidelines for colorectal cancer and polyps in patients with acromegaly. Gut 2002;51(Suppl 5):V13–4.PubMed

60.

Renehan AG, O'Dwyer ST, Shalet SM. Guidelines for colonoscopic screening in acromegaly are inconsistent with those for other high risk groups. Gut 2003;52(7):1071–2.PubMed

61.

Perry I, Stewart PM, Kane K. Colorectal screening guidelines in acromegaly. Gut 2003;52(9):1387.PubMed

62.

Mertani HC, Garcia-Caballero T, Lambert A, Gerard F, Palayer C, Boutin JM, et al. Cellular expression of growth hormone and prolactin receptors in human breast disorders. Int J Cancer 1998;79(2):202–11.PubMed

63.

Wennbo H, Tornell J. The role of prolactin and growth hormone in breast cancer. Oncogene 2000;19(8):1072–6.PubMed

64.

Kaulsay KK, Zhu T, Bennett W, Lee KO, Lobie PE. The effects of autocrine human growth hormone (hGH) on human mammary carcinoma cell behavior are mediated via the hGH receptor. Endocrinology 2001;142(2):767–77.PubMed

65.

Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M. Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Lett 1987;38(1–2):223–30.PubMed

66.

Pollak MN. Endocrine effects of IGF-I on normal and transformed breast epithelial cells: potential relevance to strategies for breast cancer treatment and prevention. Breast Cancer Res Treat 1998;47(3):209–17.PubMed

67.

Arteaga CL, Osborne CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor. Cancer Res 1989;49(22):6237–41.PubMed

68.

Yee D, Paik S, Lebovic GS, Marcus RR, Favoni RE, Cullen KJ, et al. Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol 1989;3(3):509–17.PubMed

69.

Paik S. Expression of IGF-I and IGF-II mRNA in breast tissue. Breast Cancer Res Treat 1992;22(1):31–8.PubMed

70.

Huff KK, Kaufman D, Gabbay KH, Spencer EM, Lippman ME, Dickson RB. Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells. Cancer Res 1986;46(9):4613–9.PubMed

71.

Moon HD, Simpson ME, Li CH, Evans HM. Neoplasms in rats treated with pituitary growth hormone; pulmonary and lymphatic tissues. Cancer Res 1950;10(5):297–308.PubMed

72.

Tornell J, Carlsson B, Pohjanen P, Wennbo H, Rymo L, Isaksson O. High frequency of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice created from two different strains of mice. J Steroid Biochem Mol Biol 1992;43(1–3):237–42.PubMed

73.

Hadsell DL, Murphy KL, Bonnette SG, Reece N, Laucirica R, Rosen JM. Cooperative interaction between mutant p53 and des(1–3)IGF-I accelerates mammary tumorigenesis. Oncogene 2000;19(7):889–98.PubMed

74.

Yang XF, Beamer WG, Huynh H, Pollak M. Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation. Cancer Res 1996;56(7):1509–11.PubMed

75.

Emerman JT, Leahy M, Gout PW, Bruchovsky N. Elevated growth hormone levels in sera from breast cancer patients. Horm Metab Res 1985;17(8):421–4.PubMed

76.

Peyrat JP, Bonneterre J, Hecquet B, Vennin P, Louchez MM, Fournier C, et al. Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer. Eur J Cancer 1993;29A(4):492–7.PubMed

77.

Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351(9113):1393–6.PubMed

78.

Colao A, Marzullo P, Ferone D, Spiezia S, Cerbone G, Marino V, et al. Prostatic hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab 1998;83(3):775–9.PubMed

79.

Colao A, Marzullo P, Spiezia S, Ferone D, Giaccio A, Cerbone G, et al. Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects. J Clin Endocrinol Metab 1999;84(6):1986–91.PubMed

80.

Jenkins PJ, Besser M. Clinical perspective: acromegaly and cancer: a problem. J Clin Endocrinol Metab 2001;86(7):2935–41.PubMed

81.

Cohen P, Peehl DM, Lamson G, Rosenfeld RG. Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J Clin Endocrinol Metab 1991;73(2):401–7.PubMed

82.

Iwamura M, Sluss PM, Casamento JB, Cockett AT. Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. Prostate 1993;22(3):243–52.PubMed

83.

Kaplan PJ, Mohan S, Cohen P, Foster BA, Greenberg NM. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res 1999;59(9):2203–9.PubMed

84.

Nickerson T, Chang F, Lorimer D, Smeekens SP, Sawyers CL, Pollak M. In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR). Cancer Res 2001;61(16):6276–80.PubMed

85.

Pietrzkowski Z, Wernicke D, Porcu P, Jameson BA, Baserga R. Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1. Cancer Res 1992;52(23):6447–51.PubMed

86.

Burfeind P, Chernicky CL, Rininsland F, Ilan J, Ilan J. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. Proc Natl Acad Sci U S A 1996;93(14):7263–8.PubMed

87.

Grant ES, Ross MB, Ballard S, Naylor A, Habib FK. The insulin-like growth factor type I receptor stimulates growth and suppresses apoptosis in prostatic stromal cells. J Clin Endocrinol Metab 1998;83(9):3252–7.PubMed

88.

DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A 2000;97(7):3455–60.PubMed

89.

Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO. Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 1997;76(9):1115–8.PubMed

90.

Wolk A, Mantzoros CS, Andersson SO, Bergstrom R, Signorello LB, Lagiou P, et al. Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. J Natl Cancer Inst 1998;90(12):911–5.PubMed

91.

Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279(5350):563–6.PubMed

92.

Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM, Pollak M, et al. Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 2002;94(14):1099–106.PubMed

93.

Tennant MK, Thrasher JB, Twomey PA, Birnbaum RS, Plymate SR. Insulin-like growth factor-binding protein-2 and -3 expression in benign human prostate epithelium, prostate intraepithelial neoplasia, and adenocarcinoma of the prostate. J Clin Endocrinol Metab 1996;81(1):411–20.PubMed

94.

Kanety H, Madjar Y, Dagan Y, Levi J, Papa MZ, Pariente C, et al. Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 1993;77(1):229–33.PubMed

95.

Cohen P, Peehl DM, Graves HC, Rosenfeld RG. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol 1994;142(3):407–15.PubMed

96.

Miyakawa M, Saji M, Tsushima T, Wakai K, Shizume K. Thyroid volume and serum thyroglobulin levels in patients with acromegaly: correlation with plasma insulin-like growth factor I levels. J Clin Endocrinol Metab 1988;67(5):973–8.PubMed

97.

Cheung NW, Boyages SC. The thyroid gland in acromegaly: an ultrasonographic study. Clin Endocrinol (Oxf) 1997;46(5):545–9.

98.

Junik R, Sawicka J, Kozak W, Gembicki M. Thyroid volume and function in patients with acromegaly living in iodine deficient areas. J Endocrinol Invest 1997;20(3):134–7.PubMed

99.

Kasagi K, Shimatsu A, Miyamoto S, Misaki T, Sakahara H, Konishi J. Goiter associated with acromegaly: sonographic and scintigraphic findings of the thyroid gland. Thyroid 1999;9(8):791–6.PubMed

100.

Gasperi M, Martino E, Manetti L, Arosio M, Porretti S, Faglia G, et al. Prevalence of thyroid diseases in patients with acromegaly: results of an Italian multi-center study. J Endocrinol Invest 2002;25(3):240–5.PubMed

101.

Herrmann BL, Baumann H, Janssen OE, Gorges R, Schmid KW, Mann K. Impact of disease activity on thyroid diseases in patients with acromegaly: basal evaluation and follow-up. Exp Clin Endocrinol Diabetes 2004;112(5):225–30.PubMed

102.

Tita P, Ambrosio MR, Scollo C, Carta A, Gangemi P, Bondanelli M, et al. High prevalence of differentiated thyroid carcinoma in acromegaly. Clin Endocrinol (Oxf) 2005;63(2):161–7.

103.

Wuster C, Steger G, Schmelzle A, Gottswinter J, Minne HW, Ziegler R. Increased incidence of euthyroid and hyperthyroid goiters independently of thyrotropin in patients with acromegaly. Horm Metab Res 1991;23(3):131–4.PubMed

104.

Balkany C, Cushing GW. An association between acromegaly and thyroid carcinoma. Thyroid 1995;5(1):47–50.PubMed

105.

Tramontano D, Cushing GW, Moses AC, Ingbar SH. Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves’-IgG. Endocrinology 1986;119(2):940–2.PubMed

106.

Maiorano E, Ciampolillo A, Viale G, Maisonneuve P, Ambrosi A, Triggiani V, et al. Insulin-like growth factor 1 expression in thyroid tumors. Appl Immunohistochem Mol Morphol 2000;8(2):110–9.PubMed

107.

Vella V, Sciacca L, Pandini G, Mineo R, Squatrito S, Vigneri R, et al. The IGF system in thyroid cancer: new concepts. Mol Pathol 2001;54(3):121–4.PubMed

108.

Tode B, Serio M, Rotella CM, Galli G, Franceschelli F, Tanini A, et al. Insulin-like growth factor-I: Autocrine secretion by human thyroid follicular cells in primary culture. J Clin Endocrinol Metab 1989;69:639–47.PubMed

109.

Onoda N, Ohmura E, Tsushima T, Ohba Y, Emoto N, Isozaki O, et al. Autocrine role of insulin-like growth factor (IGF)-I in a human thyroid cancer cell line. Eur J Cancer 1992;28A(11):1904–9.PubMed

110.

Minuto F, Barreca A, del Monte P, Cariola G, Torre GC, Giordano G. Immunoreactive insulin-like growth factor I (IGF-I) and IGF-I-binding protein content in human thyroid tissue. J Clin Endocrinol Metab 1989;68:621–6.PubMedCrossRef

111.

Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16(2):109–42.PubMedCrossRef

112.

Cannavo S, Curto L, Fazio R, Paterniti S, Blandino A, Marafioti T, et al. Coexistence of growth hormone-secreting pituitary adenoma and intracranial meningioma: a case report and review of the literature. J Endocrinol Invest 1993;16(9):703–8.PubMed

113.

De Menis E, Tulipano G, Villa S, Billeci D, Bonfanti C, Pollara P, et al. Development of a meningioma in a patient with acromegaly during octreotide treatment: are there any causal relationships? J Endocrinol Invest 2003;26(4):359–63.PubMed

114.

Curto L, Squadrito S, Almoto B, Longo M, Granata F, Salpietro F, et al. MRI finding of simultaneous coexistence of growth hormone-secreting pituitary adenoma with intracranial meningioma and carotid artery aneurysms: report of a case. Pituitary 2007;10:299–305.PubMed

115.

Lima GA, Gomes EM, Nunes RC, Vieira NL, Sieiro AP, Brabo EP, et al. Osteosarcoma and acromegaly: a case report and review of the literature. J Endocrinol Invest 2006;29(11):1006–11.PubMed

116.

Corcuff JB, Ogor C, Kerlan V, Rougier MB, Bercovichi M, Roger P. Ocular naevus and melanoma in acromegaly. Clin Endocrinol (Oxf) 1997;47(1):119–21.

117.

Breckenridge SM, Hamrahian AH, Faiman C, Suh J, Prayson R, Mayberg M. Coexistence of a pituitary macroadenoma and pheochromocytoma—a case report and review of the literature. Pituitary 2003;6(4):221–5.PubMed

118.

Sleilati GG, Kovacs KT, Honasoge M. Acromegaly and pheochromocytoma: report of a rare coexistence. Endocr Pract 2002;8(1):54–60.PubMed

119.

Baughan J, de Gara C, Morrish D. A rare association between acromegaly and pheochromocytoma. Am J Surg 2001;182(2):185–7.PubMed

120.

Nasushita R, Watanobe H, Goto T, Tando Y, Tanosaki M, Shiroto T, et al. A case of acromegaly accompanied by adrenal preclinical Cushing's syndrome. Endocr J 1999;46(1):133–7.PubMed

121.

Hagg E, Asplund K, Holm J. Acromegaly and multiple myeloma. Ann Intern Med 1988;109(5):437–8.PubMed

122.

Alves RH, Vaisman M, Brasil RR, Gadelha MR. Acromegaly and non-Hodgkin's lymphoma. Endocr Pract 1998;4(5):279–81.PubMed

123.

Au WY, Chow WS, Lam KS, Ko GT, Cockram CS, Kwong YL. Acute leukaemia in acromegaly patients. Br J Haematol 2000;110(4):871–3.PubMed

124.

Ritchie CM, Atkinson AB, Kennedy AL, Lyons AR, Gordon DS, Fannin T, et al. Ascertainment and natural history of treated acromegaly in Northern Ireland. Ulster Med J 1990;59(1):55–62.PubMed

125.

Minuto F, del Monte P, Barreca A, Fortini P, Cariola G, Catrambone G, et al. Evidence for an increased somatomedin-C/insulin-like growth factor I content in primary human lung tumors. Cancer Res 1986;46(2):985–8.PubMed

126.

Macauly VM, Teale JD, Everard MJ, Joshi GP, Smith IE, Millar JL. Somatomedin-C/insulin-like growth factor-I is a mitogen for human small cell lung cancer. Br J Cancer 1988;57(1):91–3.PubMed

127.

Jaques G, Rotsch M, Wegmann C, Worsch U, Maasberg M, Havemann K. Production of immunoreactive insulin-like growth factor I and response to exogenous IGF-I in small cell lung cancer cell lines. Exp Cell Res 1988;176(2):336–43.PubMed

128.

Rotsch M, Maasberg M, Erbil C, Jaques G, Worsch U, Havemann K. Characterization of insulin-like growth factor I receptors and growth effects in human lung cancer cell lines. J Cancer Res Clin Oncol 1992;118(7):502–8.PubMed

129.

Favoni RE, de Cupis A, Ravera F, Cantoni C, Pirani P, Ardizzoni A, et al. Expression and function of the insulin-like growth factor I system in human non-small-cell lung cancer and normal lung cell lines. Int J Cancer 1994;56(6):858–66.PubMed

130.

Nakanishi Y, Mulshine JL, Kasprzyk PG, Natale RB, Maneckjee R, Avis I, et al. Insulin-like growth factor-I can mediate autocrine proliferation of human small cell lung cancer cell lines in vitro. J Clin Invest 1988;82(1):354–9.PubMed

131.

Rudd MF, Webb EL, Matakidou A, Sellick GS, Williams RD, Bridle H, et al. Variants in the GH-IGF axis confer susceptibility to lung cancer. Genome Res 2006;16(6):693–701.PubMed

132.

Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999;91(2):151–6.PubMed

133.

Cosman D, Lyman SD, Idzerda RL, Beckmann MP, Park LS, Goodwin RG, et al. A new cytokine receptor superfamily. Trends Biochem Sci 1990;15(7):265–70.PubMed

134.

Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord 2006;7(4):225–35.PubMed

135.

Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, et al. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol 2005;12(9):814–21.PubMed

136.

Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, et al. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 1993;74(2):237–44.PubMed

137.

Herrington J, Smit LS, Schwartz J, Carter-Su C. The role of STAT proteins in growth hormone signaling. Oncogene 2000;19(21):2585–97.PubMed

138.

Woelfle J, Chia DJ, Rotwein P. Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. J Biol Chem 2003;278(51):51261–6.PubMed

139.

Chia DJ, Ono M, Woelfle J, Schlesinger-Massart M, Jiang H, Rotwein P. Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. J Biol Chem 2006;281(6):3190–7.PubMed

140.

Cesena TI, Cui TX, Piwien-Pilipuk G, Kaplani J, Calinescu AA, Huo JS, et al. Multiple mechanisms of growth hormone-regulated gene transcription. Mol Genet Metab 2007;90(2):126–33.PubMed

141.

Zhu T, Goh EL, Graichen R, Ling L, Lobie PE. Signal transduction via the growth hormone receptor. Cell Signal 2001;13(9):599–616.PubMed

142.

Perry JK, Emerald BS, Mertani HC, Lobie PE. The oncogenic potential of growth hormone. Growth Horm IGF Res 2006;16(5–6):277–89.PubMed

143.

Costoya JA, Finidori J, Moutoussamy S, Searis R, Devesa J, Arce VM. Activation of growth hormone receptor delivers an antiapoptotic signal: evidence for a role of Akt in this pathway. Endocrinology 1999;140(12):5937–43.PubMed

144.

Sanders EJ, Parker E, Harvey S. Retinal ganglion cell survival in development: mechanisms of retinal growth hormone action. Exp Eye Res 2006;83(5):1205–14.PubMed

145.

Jeay S, Sonenshein GE, Kelly PA, Postel-Vinay MC, Baixeras E. Growth hormone exerts antiapoptotic and proliferative effects through two different pathways involving nuclear factor-kappaB and phosphatidylinositol 3-kinase. Endocrinology 2001;142(1):147–56.PubMed

146.

MacKenzie SJ, Yarwood SJ, Peden AH, Bolger GB, Vernon RG, Houslay MD. Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes. Proc Natl Acad Sci U S A 1998;95(7):3549–54.PubMed

147.

Adams TE, Hansen JA, Starr R, Nicola NA, Hilton DJ, Billestrup N. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J Biol Chem 1998;273(3):1285–7.PubMed

148.

Michaylira CZ, Ramocki NM, Simmons JG, Tanner CK, McNaughton KK, Woosley JT, et al. Haplotype insufficiency for suppressor of cytokine signaling-2 enhances intestinal growth and promotes polyp formation in growth hormone-transgenic mice. Endocrinology 2006;147(4):1632–41.PubMed

149.

Kaulsay KK, Mertani HC, Tornell J, Morel G, Lee KO, Lobie PE. Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone. Exp Cell Res 1999;250(1):35–50.PubMed

150.

Mukhina S, Mertani HC, Guo K, Lee KO, Gluckman PD, Lobie PE. Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc Natl Acad Sci U S A 2004;101(42):15166–71.PubMed

151.

Zhu T, Starling-Emerald B, Zhang X, Lee KO, Gluckman PD, Mertani HC, et al. Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone. Cancer Res 2005;65(1):317–24.PubMed

152.

Riedemann J, Macaulay VM. IGF1R signalling and its inhibition. Endocr Relat Cancer 2006;13(Suppl 1):S33–43.PubMed

153.

Baserga R, Resnicoff M, Dews M. The IGF-I receptor and cancer. Endocrine 1997;7(1):99–102.PubMed

154.

Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004;4(7):505–18.PubMed

155.

Playford MP, Bicknell D, Bodmer WF, Macaulay VM. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc Natl Acad Sci U S A 2000;97(22):12103–8.PubMed

156.

Shen MR, Hsu YM, Hsu KF, Chen YF, Tang MJ, Chou CY. Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by alphavbeta3 integrin signaling. Carcinogenesis 2006;27(5):962–71.PubMed

157.

Zhang D, Samani AA, Brodt P. The role of the IGF-I receptor in the regulation of matrix metalloproteinases, tumor invasion and metastasis. Horm Metab Res 2003;35(11–12):802–8.PubMed

158.

Lopez T, Hanahan D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 2002;1(4):339–53.PubMed

159.

Dunn SE, Ehrlich M, Sharp NJ, Reiss K, Solomon G, Hawkins R, et al. A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res 1998;58(15):3353–61.PubMed

160.

Samani AA, Fallavollita L, Jaalouk DE, Galipeau J, Brodt P. Inhibition of carcinoma cell growth and metastasis by a vesicular stomatitis virus G-pseudotyped retrovector expressing type I insulin-like growth factor receptor antisense. Hum Gene Ther 2001;12(16):1969–77.PubMed

161.

Burger AM, Leyland-Jones B, Banerjee K, Spyropoulos DD, Seth AK. Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer 2005;41(11):1515–27.PubMed

162.

Hemminki K, Forsti A, Ji J. Incidence and familial risks in pituitary adenoma and associated tumors. Endocr Relat Cancer 2007;14(1):103–9.PubMed

163.

Hemminki K, Forsti A, Ji J. Pituitary adenoma predisposition. J Clin Endocrinol Metab 2007 (in press).

164.

Hemminki K, Li X, Dong C. Second primary cancers after sporadic and familial colorectal cancer. Cancer Epidemiol Biomarkers Prev 2001;10(7):793–8.PubMed

165.

Hemminki K, Jiang Y. Second primary neoplasms after 19281 endocrine gland tumours: aetiological links? Eur J Cancer 2001;37(15):1886–94.PubMed

166.

Vogel VG. Identifying and screening patients at risk of second cancers. Cancer Epidemiol Biomarkers Prev 2006;15(11):2027–32.PubMed

167.

Harper PA, Riddick DS, Okey AB. Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor. Biochem Pharmacol 2006;72(3):267–79.PubMed

168.

Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006;312(5777):1228–30.PubMed

169.

Yu R, Bonert V, Saporta I, Raffel LJ, Melmed S. Aryl hydrocarbon receptor interacting protein variants in sporadic pituitary adenomas. J Clin Endocrinol Metab 2006;91(12):5126–9.PubMed

170.

Iwata T, Yamada S, Mizusawa N, Golam HM, Sano T, Yoshimoto K. The aryl hydrocarbon receptor-interacting protein gene is rarely mutated in sporadic GH-secreting adenomas. Clin Endocrinol (Oxf) 2007;66(4):499–502.

171.

Barlier A, Vanbellinghen JF, Daly AF, Silvy M, Jaffrain-Rea ML, Trouillas J, et al. Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J Clin Endocrinol Metab 2007;92(5):1952–5.PubMed

172.

Daly AF, Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA, et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 2007;92(5):1891–6.PubMed

173.

Toledo RA, Lourenco DM Jr., Liberman B, Cunha-Neto MB, Cavalcanti MG, Moyses CB, et al. Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma. J Clin Endocrinol Metab 2007;92(5):1934–7.PubMed

174.

Georgitsi M, Karhu A, Winqvist R, Visakorpi T, Waltering K, Vahteristo P, et al. Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers. Br J Cancer 2007;96(2):352–6.PubMed

175.

Farrell WE. Epigenetic mechanisms of tumorigenesis. Horm Metab Res 2005;37(6):361–8.PubMed

176.

Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Genes Dev 2000;14(24):3115–25.PubMed

177.

Obaya AJ, Sedivy JM. Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci 2002;59(1):126–42.PubMed

178.

Woloschak M, Yu A, Post KD. Frequent inactivation of the p16 gene in human pituitary tumors by gene methylation. Mol Carcinog 1997;19(4):221–4.PubMed

179.

Jaffrain-Rea ML, Ferretti E, Toniato E, Cannita K, Santoro A, Di Stefano D, et al. p16 (INK4a, MTS-1) gene polymorphism and methylation status in human pituitary tumours. Clin Endocrinol (Oxf) 1999;51(3):317–25.

180.

Ogino A, Yoshino A, Katayama Y, Watanabe T, Ota T, Komine C, et al. The p15(INK4b)/p16(INK4a)/RB1 pathway is frequently deregulated in human pituitary adenomas. J Neuropathol Exp Neurol 2005;64(5):398–403.PubMed

181.

Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 1995;55(20):4525–30.PubMed

182.

Gonzalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM, et al. Methylation of the 5’′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res 1995;55(20):4531–5.PubMed

183.

Jin M, Piao Z, Kim NG, Park C, Shin EC, Park JH, et al. p16 is a major inactivation target in hepatocellular carcinoma. Cancer 2000;89(1):60–8.PubMed

184.

Kurakawa E, Shimamoto T, Utsumi K, Hirano T, Kato H, Ohyashiki K. Hypermethylation of p16(INK4a) and p15(INK4b) genes in non-small cell lung cancer. Int J Oncol 2001;19(2):277–81.PubMed

185.

Kim YI. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 2004;13(4):511–9.PubMed

186.

Evans CO, Reddy P, Brat DJ, O'Neill EB, Craige B, Stevens VL, et al. Differential expression of folate receptor in pituitary adenomas. Cancer Res 2003;63(14):4218–24.PubMed

187.

Pogribny IP, James SJ. De novo methylation of the p16INK4A gene in early preneoplastic liver and tumors induced by folate/methyl deficiency in rats. Cancer Lett 2002;187(1–2):69–75.PubMed

188.

van Engeland M, Weijenberg MP, Roemen GM, Brink M, de Bruine AP, Goldbohm RA, et al. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res 2003;63(12):3133–7.PubMed

189.

Drange MR, Fram NR, Herman-Bonert V, Melmed S. Pituitary tumor registry: a novel clinical resource. J Clin Endocrinol Metab 2000;85(1):168–74.PubMed

190.

Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol 2004;151(4):439–46.PubMed

191.

Ituarte EA, Petrini J, Hershman JM. Acromegaly and colon cancer. Ann Intern Med 1984;101(5):627–8.PubMed

192.

Pines A, Rozen P, Ron E, Gilat T. Gastrointestinal tumors in acromegalic patients. Am J Gastroenterol 1985;80(4):266–9.PubMed

193.

Ezzat S, Strom C, Melmed S. Colon polyps in acromegaly. Ann Intern Med 1991;114:754–5.PubMed

194.

Ladas SD, Thalassinos NC, Ioannides G, Raptis SA. Does acromegaly really predispose to an increased prevalence of gastrointestinal tumours? Clin Endocrinol (Oxf) 1994;41(5):597–601.

195.

Matano Y, Okada T, Suzuki A, Yoneda T, Takeda Y, Mabuchi H. Risk of colorectal neoplasm in patients with acromegaly and its relationship with serum growth hormone levels. Am J Gastroenterol 2005;100(5):1154–60.PubMed

Titel: Acromegaly: Re-thinking the cancer risk
verfasst von: Siobhan Loeper
Shereen Ezzat
Publikationsdatum: 01.03.2008
Verlag: Springer US
Erschienen in: Reviews in Endocrine and Metabolic Disorders / Ausgabe 1/2008
Print ISSN: 1389-9155
Elektronische ISSN: 1573-2606
DOI: https://doi.org/10.1007/s11154-007-9063-z

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