Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis.
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.
Giuliani
Nicola
N
Hematology and Bone Marrow Transplantation Unit, Institute of Medical Pathology, University of Parma, Italy. n_giuliani@yahoo.com
Colla
Simona
S
Lazzaretti
Mirca
M
Sala
Roberto
R
Roti
Giovanni
G
Mancini
Cristina
C
Bonomini
Sabrina
S
Lunghi
Paolo
P
Hojden
Magda
M
Genestreti
Giovenzio
G
Svaldi
Mirija
M
Coser
Paolo
P
Fattori
Pier Paolo
PP
Sammarelli
Gabriella
G
Gazzola
Gian Carlo
GC
Bataille
Regis
R
Almici
Camillo
C
Caramatti
Cecilia
C
Mangoni
Lina
L
Rizzoli
Vittorio
V
D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007952:Leukemia, Plasma Cell / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D042787:Receptor, TIE-2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C105373:MEN1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D042787:Receptor, TIE-2