Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

Abstract

Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma

“…It may well be that in active MM, plasma cells (35716% in our series) which secrete VEGF and bFGF (Bellamy et al, 1999;Vacca et al, 1999) and induce inflammatory cells to secrete their own VEGF and bFGF (Ribatti et al, 2006), continuously recruit and activate macrophages to adapt functionally, phenotypically and morphologically to become vicarious MMECs, mimicking these cells, and collaborating with them in vessel formation. This is likely minimal in nonactive MM or cannot take place in MGUS or control patients, due to the absence or small number of plasma cells (773% in nonactive MM; 472% in MGUS), hence very low levels of secreted VEGF and bFGF (Di Raimondo et al, 2000;Ribatti et al, 2006). However, when exposed to VEGF þ bFGF, macrophages of nonactive MM, MGUS and control patients underwent (albeit to a lesser extent) morphological, phenotypic and functional changes indicative of vasculogenic mimicry, becoming prone to form neovessels.…”

“…At the ultrastructural level, all macrophage types showed, as expected (Fehrenbach et al, 2005), electron-dense granules, vacuoles, lamellary bodies and lysosome-like structures. Tentatively, we suggest that the morphological differences between active MM and nonactive MM, MGUS and control macrophages are due to higher levels of VEGF and bFGF in the bone marrow milieu of active MM (Di Raimondo et al, 2000;Ribatti et al, 2006), hence to an intense, continuous paracrine stimulation of cells, as occurs in paired MMECs (Vacca et al, 2005). Macrophages of patients with active MM, exposed to VEGF þ bFGF, expressed by the seventh day typical markers (at similar levels) of paired MMECs, that is FVIII-RA, VEGFR-2 and VE-cadherin, retained their own CD14 and CD68 markers, and by 24 h they had formed vessel-like structures on the Matrigel surface, morphologically mimicking those produced by MMECs.…”

“…In fact, the mesh areas respectively were: 20.176.7, 15.775.7 and 19.376.5; lengths 58207650, 42207470 and 53207540 mm, and branching points 3877, 3775 and 2876 (all Po0.01). Vasculogenesis in MM C Scavelli et al FACS analysis of freshly isolated bone marrow monocyte/ macrophage population and immunohistochemistry of bone marrow biopsies Since MM macrophages expressed endothelial markers like MMECs and generated capillary-like structures on the Matrigel surface after VEGF þ bFGF exposure, and since both angiogenic factors, mainly secreted by MM plasma cells (Bellamy et al, 1999;Vacca et al, 1999), are present at high levels in the bone marrow (Di Raimondo et al, 2000) and act as chemotactic factors for monocytes/macrophages (Ribatti et al, 2006), we wondered whether an expansion of macrophages takes place in the MM bone marrow, and whether some of these cells express the endothelial marker FVIII-RA. (Figures 6a and b).…”

“…The in vitro and in vivo behavior of these macrophage types in active MM can thus be regarded as a 'vasculogenic mimicry', like that of melanoma and other tumor cells which form vascular channels to cater for their rapid proliferation and high need of vessels (Maniotis et al, 1999). Perhaps, in patients with active MM in whom the macrophage content in the bone marrow is markedly increased, macrophages are recruited from the bone marrow pool and/or the circulation into the VEGF þ bFGF-rich microenvironment (Ribatti et al, 2006), both factors being chemotactic for macrophages (Ribatti et al, 2006). It may well be that in active MM, plasma cells (35716% in our series) which secrete VEGF and bFGF (Bellamy et al, 1999;Vacca et al, 1999) and induce inflammatory cells to secrete their own VEGF and bFGF (Ribatti et al, 2006), continuously recruit and activate macrophages to adapt functionally, phenotypically and morphologically to become vicarious MMECs, mimicking these cells, and collaborating with them in vessel formation.…”

“…Perhaps, in patients with active MM in whom the macrophage content in the bone marrow is markedly increased, macrophages are recruited from the bone marrow pool and/or the circulation into the VEGF þ bFGF-rich microenvironment (Ribatti et al, 2006), both factors being chemotactic for macrophages (Ribatti et al, 2006). It may well be that in active MM, plasma cells (35716% in our series) which secrete VEGF and bFGF (Bellamy et al, 1999;Vacca et al, 1999) and induce inflammatory cells to secrete their own VEGF and bFGF (Ribatti et al, 2006), continuously recruit and activate macrophages to adapt functionally, phenotypically and morphologically to become vicarious MMECs, mimicking these cells, and collaborating with them in vessel formation. This is likely minimal in nonactive MM or cannot take place in MGUS or control patients, due to the absence or small number of plasma cells (773% in nonactive MM; 472% in MGUS), hence very low levels of secreted VEGF and bFGF (Di Raimondo et al, 2000;Ribatti et al, 2006).…”