Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Kimlinger TK et al.. Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression. Blood 104: 1159-1165

Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Blood (Impact Factor: 10.45). 09/2004; 104(4):1159-65. DOI: 10.1182/blood-2003-11-3811
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We compared the angiogenic potential of bone marrow plasma and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors on plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (NMM). Cytokine and cytokine-receptor expression was studied by bone marrow immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (RT-PCR) on sorted plasma cells, and quantitative Western blot analysis. Bone marrow angiogenic potential was studied using a human in vitro angiogenesis assay. The expression levels of VEGF, bFGF, and their receptors were similar among MGUS, SMM, and NMM. Sixty-one percent of NMM samples stimulated angiogenesis in the in vitro angiogenesis assay compared with SMM (0%) and MGUS (7%) (P <.001). Importantly, 63% of MGUS samples inhibited angiogenesis compared with SMM (43%) and NMM (4%) (P <.001). The inhibitory activity was heat stable, not overcome by the 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 plasma cells. The active inhibition of angiogenesis in MGUS is lost with progression, and the angiogenic switch from MGUS to NMM may involve a loss of inhibitory activity.

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Available from: Shaji K Kumar, Dec 12, 2014
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    • "Only RNAs with clear 18S and 28S peaks were used. VEGF-A expression was studied using semi-quantitative RT-PCR as described previously [15]. Briefly, RT-PCR was performed as a multiplex using the Titan One Tube RT-PCR System according to the manufacturer’s instructions (Roche Diagnostics GmbH, Mannheim Germany). "
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    ABSTRACT: Background Symptomatic multiple myeloma (MM) evolves from an asymptomatic precursor state termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Angiogenesis plays a key role in the pathogenesis of MM but there are very limited data for angiogenesis in SMM. Material/Methods We measured the circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and angiogenin in 54 patients with SMM. The results were compared with those of 27 MGUS patients, 55 MM patients, and 22 healthy controls. The expression of VEGF-A gene was also evaluated in 10 patients with SMM, 10 with symptomatic MM, and 10 with MGUS. Results The ratio of circulating Ang-1/Ang-2 was reduced in MM patients with symptomatic disease due to a dramatic increase of Ang-2 (p<0.001), but not in patients with SMM or MGUS, in whom it did not differ compared to controls. VEGF and angiogenin were increased in all patients compared to controls. However, circulating VEGF was higher in symptomatic MM compared to SMM and MGUS, while angiogenin was reduced. There were no differences in the expression of VEGF-A among the 3 patients categories. Conclusions SMM has a circulating angiogenic cytokine profile similar to that of MGUS, but has altered profile compared to symptomatic MM. Thus, in the progression of MGUS to SMM, circulating angiogenic cytokines seem to be the same. On the contrary, in symptomatic myeloma, the alterations of angiopoietins along with VEGF contribute to myeloma cell growth, supporting the target of these molecules for the development of novel anti-myeloma agents.
    Medical science monitor: international medical journal of experimental and clinical research 12/2013; 19:1188-94. DOI:10.12659/MSM.889752 · 1.43 Impact Factor
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    • "EC-like macrophages and apparently typical macrophages contributed sizably to form the neovessel wall in patients with active MM, whereas their vascular supply was minimal in nonactive MM and absent in MGUS patients. These data suggest that in active MM, macrophages contribute to neovascularization through a vasculogenic pathway, and that in nonactive MM and MGUS, they are prone to behave accordingly, marching in step with progression, hence, with the vascular switch [29]. MM-associated macrophages present morphological differences from those from nonactive MM or MGUS and benign anemia patients; they displayed oblong and spindle shape with thin cytoplasmic extroversions, some of which were either arranged to form a microvessel-like lumen or anastomosed with each other and with those of nearby macrophages to form tube-like structures. "
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    ABSTRACT: Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.
    Journal of Oncology 01/2013; 2013:183602. DOI:10.1155/2013/183602
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    • "VEGF triggered effects in MM cells are predominantly mediated via VEGFR 1 and in endothelial cells, predominantly via VEGF R2 [44]. Rajkumar et al. showed a gradual increase of bone marrow angiogenesis along the disease spectrum from monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM, newly diagnosed MM and relapsed MM [45], though the expression levels of VEGF, bFGF, and their receptors were similar among MGUS, smoldering MM, and newly diagnosed MM [46], rising the hypothesis that MVD increase in plasma cell neoplasias could be rather a function of chronology. "
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    ABSTRACT: New blood vessel formation (angiogenesis) is not only essential for the growth of solid tumors but there is also emerging evidence that progression of hematological malignancies like multiple myeloma, acute leukemias, and myeloproliferative neoplasms, also depends on new blood vessel formation. Anti-angiogenic strategies have become an important therapeutic modality for solid tumors. Several anti-angiogenic agents targeting angiogenesis-related pathways like monoclonal antibodies, receptor tyrosine kinase inhibitors, immunomodulatory drugs, and proteasome inhibitors have been entered clinical trials or have been already approved for the treatment of hematological malignancies as well and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hematological malignancies and clinical trials with novel therapeutic approaches targeting angiogenesis.
    Journal of Angiogenesis Research 06/2010; 2(1):10. DOI:10.1186/2040-2384-2-10
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