title: The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis.
abstract: 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.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: K A
authors.initials: KA
authors.lastname: Kocemba
authors.forename: H
authors.initials: H
authors.lastname: van Andel
authors.forename: A
authors.initials: A
authors.lastname: de Haan-Kramer
authors.forename: K
authors.initials: K
authors.lastname: Mahtouk
authors.forename: R
authors.initials: R
authors.lastname: Versteeg
authors.forename: M J
authors.initials: MJ
authors.lastname: Kersten
authors.forename: M
authors.initials: M
authors.lastname: Spaargaren
authors.forename: S T
authors.initials: ST
authors.lastname: Pals
mesh_terms: D053607:Adrenomedullin / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D053607:Adrenomedullin