Am J Blood Res 2011;1(1):76-89

Review Article
Bone marrow angiogenesis and progression in multiple myeloma

Roberto Ria, Antonia Reale, Annunziata De Luisi, Arianna Ferrucci, Michele Moschetta, Angelo Vacca

Medizinische Klinik A, Universitätsklinikum Münster, Münster, Germany

Received May 21, 2011; accepted June 6, 2011; Epub June 8, 2011; published June 15, 2011

Abstract: Multiple myeloma plasma cells home and expand in the bone marrow where cause an unbalanced bone
remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of
patients. A clinically relevant aspect of the interactions of multiple myeloma plasma cells in the bone marrow
microenvironment is neovascularization, a constant hallmark of disease progression. This process is only partially supported
by factors such as vascular endothelial growth factor, fibroblast growth factor-2 and metalloproteinases, which are directly
secreted by the tumor cells. In fact, the presence in the bone marrow microenvironment of cytokines, in particular interleukin-6,
as a consequence of plasma cell-stromal cell interactions, induces the production and secretion of angiogenic factors by
other cells present in the bone microenvironment, thus contributing to the angiogenic switch during the progression of the
disease. Near angiogenesis vasculogenesis occur in the bone marrow of myeloma patients and contribute to the vascular
three formation. In the bone marrow of myeloma patients haematopoietic stem cells are recruited and induced to differentiate
into endothelial cells by the angiogenic cytokines present in the microenvironment. Myeloma plasma cells also induce
angiogenesis indirectly via recruitment and activation of stromal inflammatory cells (i.e.: macrophages and mast cells) to
secrete their own angiogenic factors. They are recruited and activated by tumor plasma cells through the secretion of
fibroblast growth factor-2, interleukin-8, and other chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells
are activated they secrete their angiogenic factors: fibroblast growth factor-2, vascular endothelial growth factor, granulocyte-
colony stimulating factor, granulocyte macrophage-colony stimulating factor, which contribute to enhance the tumor
neovascularization. Finally, myeloma macrophages when exposed to vascular endothelial growth factor and fibroblast growth
factor-2 secreted by plasma cells shows vasculogenic ability and acquire endothelial cell markers and transform into cells
functionally and phenotypically similar to paired bone marrow endothelial cells. So they participate to the formation of the bone
marrow capillary network (vasculogenic mimicry). (AJBR1105006).

Keywords: Angiogenesis; endothelial cells; fibroblast growth factor-2; multiple myeloma; tumor progression; vasculogenesis;
vascular endothelial growth factor

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Address all correspondence to:
Roberto Ria, MD
Department of Internal Medicine and Human Oncology
Section of Internal Medicine and Clinical Oncology
University of Bari “Aldo Moro” Medical School
Policlinico - Piazza Giulio Cesare, 11
I-70124 Bari, Italy.
Tel: +39.080.5593106
Fax: +39.080.5478859
E-mail:
ria@dimo.uniba.it
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