Bone marrow angiogenesis in patients with active multiple myeloma.
Factor VIII-related antigen (FVIII-RA)-positive microvessel areas were measured by both immunohistochemistry and computerized image analysis in patients with active multiple myeloma (MM), nonactive MM, and monoclonal gammopathies of undetermined significance (MGUS). A five-to sixfold larger area was found in patients with active MM compared to the other two groups. Aquaporin 1 (AQP1)-positive microvessel areas, measured with the same techniques on adjacent tissue sections, were also increased in active MM, and tended to be larger than and closely correlated with the FVIII-RA areas. Numerous mast cells were found in the bone marrow of active MM patients, and counts were strictly correlated with the microvessel density. The conditioned medium (CM) of bone marrow plasma cells from active MM patients stimulated endothelial cell proliferation and chemotaxis, monocyte chemotaxis, and angiogenesis in vivo (assessed by the chick embryo chorioallantoic membrane [CAM] system) more strongly and frequently than the CM of patients with nonactive MM and MGUS. Immunoassay of plasma cell lysates gave significantly higher levels of fibroblast growth factor-2 (FGF-2) in patients with active MM than in the other two groups, and a neutralizing anti-FGF-2 antibody inhibited by 46% to 68% the biological activity exerted by the CM in vitro and in the CAM. In situ hybridization of bone marrow plasma cells and zymography of CM showed that patients with active MM express higher levels of matrix metalloproteinase-2 (MMP-2) mRNA and protein than those with nonactive MM and MGUS, whereas MMP-9 expression and secretion overlapped in all groups. Overall data indicate that patients with active MM represent the vascular phase of plasma cell tumors that is induced, at least partly, through FGF-2 and MMP-2. Mast cells possibly contribute to the vascular phase via angiogenic factors in their secretory granules. Both angiogenesis and MMP-2 secretion can account for intramedullary and extramedullary spreading of plasma cells in patients with active MM.
Vacca
A
A
Department of Biomedical Sciences and Oncology, University of Bari Medical School, Policlinico-Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
Ribatti
D
D
Roccaro
A M
AM
Frigeri
A
A
Dammacco
F
F
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D051398:Aquaporin 1; D020346:Aquaporins / Q000378:metabolism; D001789:Blood Group Antigens; D001853:Bone Marrow / Q000098:blood supply* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008407:Mast Cells / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009101:Multiple Myeloma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010265:Paraproteinemias / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D013925:Thromboplastin / Q000378:metabolism
C496020:AQP1 protein, human; D043925:Angiogenesis Inducing Agents; D020346:Aquaporins; D001789:Blood Group Antigens; D016222:Fibroblast Growth Factor 2; D051398:Aquaporin 1; D013925:Thromboplastin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9