title: Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression.
abstract: We compared the angiogenic potential of bone marrow plasma and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors on plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (NMM). Cytokine and cytokine-receptor expression was studied by bone marrow immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (RT-PCR) on sorted plasma cells, and quantitative Western blot analysis. Bone marrow angiogenic potential was studied using a human in vitro angiogenesis assay. The expression levels of VEGF, bFGF, and their receptors were similar among MGUS, SMM, and NMM. Sixty-one percent of NMM samples stimulated angiogenesis in the in vitro angiogenesis assay compared with SMM (0%) and MGUS (7%) (P <.001). Importantly, 63% of MGUS samples inhibited angiogenesis compared with SMM (43%) and NMM (4%) (P <.001). The inhibitory activity was heat stable, not overcome by the addition of VEGF, and corresponded to a molecular weight below 10 kd by size-exclusion chromatography. Our results suggest that increasing angiogenesis from MGUS to NMM is, at least in part, explained by increasing tumor burden rather than increased expression of VEGF/bFGF by individual plasma cells. The active inhibition of angiogenesis in MGUS is lost with progression, and the angiogenic switch from MGUS to NMM may involve a loss of inhibitory activity.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Michael
authors.initials: M
authors.lastname: Timm
authors.forename: Jessica
authors.initials: J
authors.lastname: Haug
authors.forename: Linda
authors.initials: L
authors.lastname: Wellik
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Kimlinger
authors.forename: Philip R
authors.initials: PR
authors.lastname: Greipp
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
mesh_terms: D001853:Bone Marrow / Q000098:blood supply* / Q000473:pathology; D001856:Bone Marrow Examination; D016207:Cytokines / Q000032:analysis / Q000235:genetics*; D018450:Disease Progression; D016222:Fibroblast Growth Factor 2 / Q000032:analysis / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D009389:Neovascularization, Pathologic; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics / Q000494:pharmacology
chemical_list: D016207:Cytokines; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040262:Receptors, Vascular Endothelial Growth Factor