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Blood, 15 August 2004, Vol. 104, No. 4, pp. 1159-1165.
Prepublished online as a Blood First Edition Paper on May 6, 2004; DOI 10.1182/blood-2003-11-3811.
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Submitted November 10, 2003
Accepted April 22, 2004
Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: Evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression
Shaji Kumar, Thomas E Witzig, Michael Timm, Jessica Haug, Linda Wellik, Teresa K Kimlinger, Philip R Greipp, and S V Rajkumar*
Hematology, Mayo Clinic, Rochester, MN, USA
* Corresponding author; email: rajkumar.vincent{at}mayo.edu.
We compared the angiogenic potential of bone marrow plasma and the expression of VEGF, bFGF and their receptors on plasma cells (PCs) from patients with MGUS, smoldering myeloma (SMM), and newly diagnosed MM (NMM). Cytokine and cytokine-receptor expression was studied by bone marrow immunohistochemistry, quantitative RT-PCR on sorted PCs, and by quantitative Western Blotting. Bone marrow angiogenic potential was studied using a human in vitro angiogenesis assay. The expression level of VEGF, bFGF and their receptors was similar between MGUS, SMM, and NMM. Sixty-one percent of NMM samples stimulated angiogenesis in the in vitro angiogenesis assay, compared to SMM (0%) and MGUS (7%), P<0.001. Importantly, 63% of MGUS samples inhibited angiogenesis, compared to SMM (43%) and NMM (4%), P<0.001. The inhibitory activity was heat stable, not overcome by 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 PCs. There is active inhibition of angiogenesis in MGUS, which is lost with progression. The angiogenic switch from MGUS to NMM may involve loss of inhibitory activity.
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