Abstract
Adrenomedullin is a multi-functional polypeptide hormone. Its involvement in angiogenesis and vasodilator action support the hypothesis that adrenomedullin may be a secretory product of neuroendocrine tumors and contribute to tumor progression. Plasma levels of adrenomedullin were measured by radioimmunoassay in 46 patients with neuroendocrine carcinomas of the gastroenteropancreatic and bronchial system. Tissue expression of adrenomedullin was studied using monoclonal antibodies on pretreated paraffin embedded tissues in a group of 31 patients. Adrenomedullin plasma levels were significantly elevated in patients compared to healthy age-matched controls (p < 0.001). The highest plasma levels were found in patients with neuroendocrine carcinomas of bronchial, midgut and unknown origin. Patients with progressive disease had higher plasma levels than patients with stable disease (p < 0.001). Of the examined tumor samples, 55 % showed cytoplasmic staining for adrenomedullin > 5 % of the total tumor area. Plasma levels and tissue expression of adrenomedullin did not correlate with functional activity of the tumors or presence of the carcinoid syndrome, but did with tumor progression (p < 0.001 and p < 0.014). In conclusion, plasma and tissue expression of the angiogenic peptide adrenomedullin are predictive of tumor progression in patients with neuroendocrine carcinomas. Adrenomedullin might represent a useful prognostic marker in patients with neuroendocrine carcinomas.
Key words
Angiogenesis · neuroendocrine tumor · immunohistochemistry · radioimmunoassay · prognostic marker
References
-
1 Solcia E, Klöppel G, Sobin L H. Histological typing of endocrine tumors. In: World Health Organization, 2nd edn. Heidelberg; 2000
-
2
Modlin I M, Lye K D, Kidd M.
A 5-decade analysis of 13,715 carcinoid tumors.
Cancer.
2003;
97
934-959
-
3
Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T.
Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma.
Biochem Biophys Res Commun.
1993;
192
553-560
-
4
Satoh F, Takahashi K, Murakami O, Totsune K, Sone M, Ohneda M, Abe K, Miura Y, Hayashi Y, Sasano H.
Adrenomedullin in human brain, adrenal glands and tumor tissues of pheochromocytoma, ganglioneuroblastoma and neuroblastoma.
J Clin Endocrinol Metabol.
1995;
80
1750-1752
-
5
Martinez A, Miller M J, Unsworth E J, Siegfried J M, Cuttitta F.
Expression of adrenomedullin in normal human lung and in pulmonary tumors.
Endocrinology.
1995;
136
4099-4105
-
6
Kato H, Shichiri M, Marumo F, Hirata Y.
Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells.
Endocrinology.
1997;
138
2615-2620
-
7
Ehlenz K, Koch B, Preuss P, Simon B, Koop I, Lang R E.
High levels of circulating adrenomedullin in severe illness: correlation with C-reactive protein and evidence against the adrenal medulla as site of origin. Exp Clin Endocrinol.
Diabetes.
1997;
105
156-162
-
8
Zudaire E, Martínez A, Cuttitta F.
Adrenomedullin and cancer.
Regulatory Peptides.
2003;
112
175-183
-
9
Bouck N, Stellmach V, Hsu S C.
How tumors become angiogenic.
Adv Cancer Res.
1996;
69
135-174
-
10
Hanahan D, Folkman J.
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
Cell.
1996;
86
353-364
-
11
Nikitenko L L, MacKenzie I Z, Rees M C, Bicknell R.
Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium. Mol Hum.
Reprod.
2000;
6
811-819
-
12
Hague S, Zhang L, Oehler M K, Manek S, MacKenzie I Z, Bicknell R, Rees M C.
Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density. Clin.
Cancer Res.
2000;
6
2808-2814
-
13
Klöppel G, Peren A, Heitz P U.
The gastroenteropancreatic neuroendocrine cell system. WHO system.
Ann New York Acad Sci.
2004;
1014
13-27
-
14
Martinez A, Weaver C, Lopez J, Bhathena S J, Elsasser T H, Miller M J, Moody T W, Unsworth E J, Cuttitta F.
Regulation of insulin secretion and blood glucose metabolism by adrenomedullin.
Endocrinology.
1996;
137
2626-2632
-
15
Zhao Y, Hague S, Manek S, Zhang L, Bicknell R, Rees M C.
PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium.
Oncogene.
1998;
16
409-415
-
16
Martinez A, Vos M, Guedez L, Kaur G, Chen Z, Garayoa M, Pio R, Moody T, Stetler-Stevenson W G, Kleinman H K, Cuttitta F.
The effects of adrenomedullin overexpression in breast tumor cells.
J Natl Cancer Inst.
2002;
94
1226-1237
-
17
Rees M, Hague S, Oehler M K, Bicknell R.
Regulation of endometrial angiogenesis.
Climacteric.
1999;
2
52-58
-
18
Ouafik S, Sauze F, Boudouresque O, Chinot C, Delfino F, Fina F, Vuaroqueaux V, Dussert C, Palmari J, Dufour H, Grisoli F, Casellas P, Brunner N, Martin P M.
Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo.
Am J Pathol.
2002;
160
1279-1292
-
19
Rocchi P, Boudouresque F, Zamora A J, Muracciole X, Lechevallier E, Martin P M, Ouafik L.
Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines.
Cancer Res.
2001;
61
1196-1206
-
20
Miller M J, Martinez A, Unsworth E J, Thiele C J, Moody T W, Elsasser T, Cuttitta F.
Adrenomedullin expression in human tumor cell lines. Its potential role as an autocrine growth factor.
J Biol Chem.
1996;
271
22 345-22 351
-
21
Cheung B, Leung R.
Elevated plasma levels of human adrenomedullin in cardiovascular, respiratory, hepatic and renal disorders.
Clin Sci (Colch).
1997;
92
59-62
-
22
Kuwasako K, Kida O, Kitamura K, Kato J, Eto T.
Plasma adrenomedullin in cerebrovascular disease: a possible indicator of endothelial injury.
Int Angiol.
1997;
16
272-279
M. E. Pavel, M. D.
Department of Medicine I, Division of Endocrinology
University of Erlangen-Nürnberg · Ulmenweg 18 · 91054 Erlangen · Germany
Fax: +49(9131)8535148 ·
eMail: marianne.pavel@med1.imed.uni-erlangen.de
