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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3064-3073
Bone Marrow Neovascularization, Plasma Cell Angiogenic Potential, and
Matrix Metalloproteinase-2 Secretion Parallel Progression of Human
Multiple Myeloma
Angelo Vacca,
Domenico Ribatti,
Marco Presta,
Monica Minischetti,
Monica Iurlaro,
Roberto Ria,
Adriana Albini,
Federico Bussolino, and
Franco Dammacco
From the Department of Biomedical Sciences and Human Oncology, and
the Institute of Human Anatomy, Histology and Embryology, School of
Medicine, University of Bari, Bari; the Department of Biomedical
Sciences and Biotechnology, School of Medicine, University of Brescia,
Brescia; Advanced Biotechnology Center, National Institute for Cancer
Research, Genova; and the Institute for Cancer Research and Treatment
(IRCC), School of Medicine, University of Torino, Torino, Italy.
To assess whether the progression of plasma cell tumors is
accompanied by angiogenesis and secretion of matrix-degrading enzymes, bone marrow biopsy specimens from 20 patients with monoclonal gammopathy of undetermined significance (MGUS), 18 patients with nonactive multiple myeloma (MM), and 26 patients with active MM were
evaluated for their angiogenic potential and matrix-metalloproteinase (MMP) production. A fivefold increase of the factor VIII+
microvessel area was measured by a planimetric method of point counting
in the bone marrow of patients with active MM as compared with
nonactive MM and MGUS patients (P < .01). When serum-free conditioned media (CM) of plasma cells isolated from the bone marrow of
each patient were tested in vivo for their angiogenic activity in the
chick embryo chorioallantoic membrane (CAM) assay, the incidence
of angiogenic samples was significantly higher (P < .01) in the active MM group (76%) compared with nonactive
MM (33%) and MGUS (20%) groups. Moreover, a linear correlation
(P < .01) was found between the extent of vascularization of
the bone marrow of a given patient and the angiogenic activity exerted in the CAM assay by the plasma cells isolated from the same bone marrow. In vitro, a significantly higher fraction of the plasma cell CM
samples from the active MM group stimulated human umbilical vein
endothelial cell (HUVEC) proliferation (53%, P < .01),
migration (42%, P < .05), and/or monocyte chemotaxis (38%,
P < .05) when compared with nonactive MM and MGUS groups
(ranging between 5% and 15% of the samples). Also, immunoassay of
plasma cell extracts showed significantly higher (P < .01)
levels of the angiogenic basic fibroblast growth factor (FGF)-2 in the
active MM patients than in nonactive MM and MGUS patients (153 ± 59, 23 ± 17, and 31 ± 18 pg FGF-2/100 µg of protein, respectively).
Accordingly, neutralizing anti-FGF-2 antibody caused a significant
inhibition (ranging from 54% to 68%) of the biological activity
exerted on cultured endothelial cells and in the CAM assay by plasma
cell CM samples from active MM patients. Finally, in situ hybridization of bone marrow plasma cells and gelatin-zymography of their CM showed
that active MM patients express significantly higher (P < .01) levels of MMP-2 mRNA and protein when compared with nonactive MM
and MGUS patients, whereas MMP-9 expression was similar in all groups.
Taken together, these findings indicate that the progression of plasma
cell tumors is accompanied by an increase of bone marrow neovascularization. This is paralleled by an increased angiogenic and
invasive potential of bone marrow plasma cells, which is dependent, at
least in part, by FGF-2 and MMP-2 production. Induction of angiogenesis
and secretion of MMPs by plasma cells in active disease may play a role
in their medullary and extramedullary dissemination, raising the
hypothesis that angiostatic/anti-MMP agents may be used for therapy of MM.
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