title: Induction of angiogenesis by normal and malignant plasma cells.
abstract: Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
authors.affiliation: Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany. dirk.hose@med.uni-heidelberg.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.forename: Jérôme
authors.initials: J
authors.lastname: Moreaux
authors.forename: Tobias
authors.initials: T
authors.lastname: Meissner
authors.forename: Anja
authors.initials: A
authors.lastname: Seckinger
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Karène
authors.initials: K
authors.lastname: Mahtouk
authors.forename: Jens
authors.initials: J
authors.lastname: Hillengass
authors.forename: Thierry
authors.initials: T
authors.lastname: Rème
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Michael
authors.initials: M
authors.lastname: Hundemer
authors.forename: Maud
authors.initials: M
authors.lastname: Condomines
authors.forename: Uta
authors.initials: U
authors.lastname: Bertsch
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rossi
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
authors.forename: Thomas
authors.initials: T
authors.lastname: Möhler
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics; D043165:Angiostatic Proteins / Q000235:genetics; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology; D001853:Bone Marrow / Q000098:blood supply; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009101:Multiple Myeloma / Q000098:blood supply* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000473:pathology* / Q000502:physiology*
chemical_list: D042501:Angiogenic Proteins; D043165:Angiostatic Proteins