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      Adrenomedullin and tumour angiogenesis

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          Abstract

          The angiogenic activity of peptide adrenomedullin (AM) was first shown in 1998 . Since then, a number of reports have confirmed the ability of AM to induce the growth and migration of isolated vascular endothelial and smooth muscle cells in vitro and to promote angiogenesis in xenografted tumours in vivo. In addition, knockout murine models point to an essential role for AM in embryonic vasculogenesis and ischaemic revascularisation. AM expression is upregulated by hypoxia (a typical feature of solid tumours) and a potential role as a regulator of carcinogenesis and tumour progression has been proposed based on studies in vitro and in animal models. Nevertheless, translational research on AM, and in particular, confirmation of its importance in the vascularisation of human tumours has lagged behind. In this commentary, we review current progress and potential directions for future research into the role of AM in tumour angiogenesis.

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          Most cited references35

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          Adrenomedullin, a multifunctional regulatory peptide.

          Since the discovery of adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing adrenomedullin far exceeding those that do not. In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting adrenomedullin and of the mechanisms regulating gene expression. The data on circulating adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative adrenomedullin receptor clones and signal transduction pathways are described. In Section IV the various actions of adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered. Finally, in Section V, we consider some unresolved issues and propose future areas for research.
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            Cloning and characterization of cDNA encoding a precursor for human adrenomedullin.

            Adrenomedullin is a novel hypotensive peptide recently isolated from human pheochromocytoma. Since a high concentration of immunoreactive adrenomedullin was found in pheochromocytoma tissue, the cDNA library of pheochromocytoma was constructed, and the cDNA clone encoding an adrenomedullin precursor was isolated and sequenced. The precursor for human adrenomedullin (human preproadrenomedullin) is 185 amino acids in length, including an adrenomedullin sequence. Proadrenomedullin (proAM) contains a unique twenty amino acid sequence followed by Gly-Lys-Arg in the N-terminal region. It is possible that a novel 20 residues peptide, termed "proadrenomedullin N-terminal 20 peptide" (proAM-N20) whose carboxy terminus may be Arg-NH2, is processed from proadrenomedullin. By RNA blot analysis, human adrenomedullin mRNA was found to be highly expressed in several tissues including adrenal medulla, ventricle, lung and kidney as well as pheochromocytoma.
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              Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.

              Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                0007-0920
                1532-1827
                10 January 2006
                16 January 2006
                : 94
                : 1
                : 1-7
                Affiliations
                [1 ]Nuffield Department of Obstetrics and Gynaecology, The University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
                [2 ]Nuffield Department of Clinical Laboratory Sciences, The University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
                [3 ]Molecular Angiogenesis Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, The University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
                [4 ]Institute for Biomedical Research, Birmingham University Medical School, Edgbaston, Birmingham B15 2TT, United Kingdom
                Author notes
                [* ]Author for correspondence: leonid.nikitenko@ 123456obs-gyn.ox.ac.uk
                Article
                6602832
                10.1038/sj.bjc.6602832
                2361077
                16251875
                55a40a7c-5140-4c87-98aa-69c8ca41e98c
                Copyright 2006, Cancer Research UK
                History
                : 08 August 2005
                : 30 August 2005
                : 23 September 2005
                Categories
                Reviews

                Oncology & Radiotherapy
                crlr,tumour,endothelial cell,adrenomedullin,cl,angiogenesis
                Oncology & Radiotherapy
                crlr, tumour, endothelial cell, adrenomedullin, cl, angiogenesis

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