The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis

• Published in: Leukemia Vol. 27; no. 8; pp. 1729 - 1737
• Main Authors: Kocemba, K A, van Andel, H, de Haan-Kramer, A, Mahtouk, K, Versteeg, R, Kersten, M J, Spaargaren, M, Pals, S T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2013; Nature Publishing Group
• Subjects: 631/92/555; 692/1807/244; 692/699/67/1990/804; 692/699/67/2328; Adrenomedullin; Adrenomedullin - genetics; Angiogenesis; Bone marrow; Cancer Research; Cell Line, Tumor; Cell proliferation; Cobalt; Cobalt chloride; Critical Care Medicine; Development and progression; Disease Progression; Endothelial cells; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Hematology; Humans; Hypoxia; Hypoxia - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Identification and classification; Intensive; Internal Medicine; Leukemia; Medicine; Medicine & Public Health; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neovascularization; Neovascularization, Pathologic - genetics; NF-kappa B - genetics; NF-kappa B - metabolism; Oncology; original-article; Pathogenesis; Peptides; Physiological aspects; Plasma; Plasma cells; Subgroups; Transcription, Genetic; United States > US; Netherlands; hypoxia; adrenomedullin; myeloma; angiogenesis
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.76

In multiple myeloma (MM), angiogenesis is strongly correlated to disease progression and unfavorable outcome, and may be promoted by bone marrow hypoxia. Employing gene-expression profiling, we here identified the pro-angiogenic factor adrenomedullin (AM) as the most highly upregulated gene in MM cells exposed to hypoxia. Malignant plasma cells from the majority of MM patients, belonging to distinct genetic subgroups, aberrantly express AM. Already under normoxic conditions, a subset of MM highly expressed and secreted AM, which could not be further enhanced by hypoxia or cobalt chloride-induced stabilization of hypoxia-inducible factor (HIF)1α. In line with this, expression of AM did not correlate with expression of a panel of established hypoxia-/HIF1α-target genes in MM patients. We demonstrate that MM-driven promotion of endothelial cell proliferation and tube formation is augmented by inducible expression of AM and strongly repressed by inhibition of endogenous and hypoxia-induced AM activity. Together, our results demonstrate that MM cells, both in a hypoxia-dependent and -independent fashion, aberrantly express and secrete AM, which can mediate MM-induced angiogenesis. Thus, AM secretion can be a major driving force for the angiogenic switch observed during MM evolution, which renders AM a putative target for MM therapy.