Abstract
Patients with multiple myeloma (MM) have increased bone marrow (BM) angiogenesis; however, the proangiogenic properties of myeloma cells and the mechanisms of MM-induced angiogenesis are not completely clarified. The angiopoietin system has been identified as critical in the regulation of vessel formation. In this study we have demonstrated that myeloma cells express several proangiogenic factors, and, in particular, we found that angiopoietin-1 (Ang-1), but not its antagonist Ang-2, was expressed by several human myeloma cell lines (HMCLs) at the mRNA and the protein levels. In a transwell coculture system, we observed that myeloma cells up-regulated the Ang-1 receptor Tie2 in human BM endothelial cells. Moreover, in an experimental model of angiogenesis, the conditioned medium of HMCLs significantly stimulated vessel formation compared with control or vascular endothelial growth factor (VEGF) treatment. The presence of anti-Tie2 blocking antibody completely blunted the proangiogenic effect of XG-6. Finally, our in vitro results were supported by the in vivo finding of Ang-1, but not Ang-2, mRNA and protein expression in purified MM cells obtained from approximately 47% of patients and by high BM angiogenesis in patients with MM positive for Ang-1, suggesting that the angiopoietin system could be involved, at least in part, in MM-induced angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Angiogenesis Inducing Agents / analysis
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Angiogenesis Inducing Agents / biosynthesis
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Angiogenesis Inducing Agents / genetics
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Angiogenesis Inducing Agents / physiology*
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Angiopoietin-1
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Angiopoietin-2
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Bone Marrow Cells / metabolism
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Coculture Techniques
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Culture Media, Conditioned / pharmacology
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Endothelial Growth Factors / pharmacology
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Endothelium / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Intercellular Signaling Peptides and Proteins / pharmacology
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Leukemia, Plasma Cell / metabolism
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Leukemia, Plasma Cell / pathology
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Lymphokines / pharmacology
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Middle Aged
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Multiple Myeloma / blood supply
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism*
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Multiple Myeloma / pathology
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Neoplasm Proteins / physiology*
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Proto-Oncogene Proteins*
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Receptor, TIE-2
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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ANGPT1 protein, human
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Angiogenesis Inducing Agents
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Angiopoietin-1
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Angiopoietin-2
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Antibodies, Monoclonal
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Culture Media, Conditioned
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Endothelial Growth Factors
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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MEN1 protein, human
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Membrane Glycoproteins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor, TIE-2