Potential role of FLT3-ligand in the angiogenic process of multiple myeloma.

The aim of the study was to evaluate serum levels of FLT3-ligand (FLT3-L), a soluble molecule in bone marrow (BM), participating actively in hematopoiesis, in relation with angiogenic factors in multiple myeloma (MM) patients. We measured, in 70 patients with active MM and in 38 of them who responded to conventional therapy, serum levels of FLT3-L, along with known angiogenic factors, such as VEGF, endoglin, TNF-alpha and HGF (with ELISA) and BM microvascular density (MVD), estimating the immunohistochemical expression of CD31. All pre-treatment values were higher in active MM patients compared to controls (p<0.001 for all cases), in parallel with both International Staging System and Durie-Salmon stages (p<0.001 for all cases). Moreover, levels of FLT3-L correlated positively with all soluble angiogenic factors, as well with MVD (p<0.0001 for all cases). Post-treatment values of FLT3-L decreased significantly in responders to therapy (p<0.001). The underlying relation of MM angiogenesis with FLT3-L may result from the fact that BM microvasculature is a major source of FLT3-L, both in BM niche and probably in peripheral blood. Our results suggest that serum levels of FLT3-L may be used as angiogenic marker in MM patients.

Circulating serum levels of IL-20 in multiple myeloma patients: its significance in angiogenesis and disease activity.

Angiogenesis is an important hallmark in multiple myeloma (MM) pathogenesis, with the participation of various versatile molecules. Interleukin-20 (IL-20) is a pro-inflammatory cytokine with diverse angiogenic properties. Our purpose was to estimate the possible impact of IL-20 on MM angiogenesis and disease activity. We measured serum levels of IL-20 along with levels of vascular endothelial growth factor (VEGF), basic-fibroblast growth factor and angiopoietin 2 in 58 active MM myeloma patients, in 32 of them who responded to bortezomib-based therapy and in 20 controls. We also measured bone marrow microvasclular density (MVD) by immunohistochemical method. Serum levels of all cytokines and bone marrow MVD were higher in active MM patients compared to controls and responders to bortezomib-based therapy (p < 0.001 in all cases). They were also in parallel with International Staging System stages (p < 0.001 for all cases). Serum levels of IL-20 correlated positively with levels of angiogenic cytokines and bone marrow MVD (p < 0.01 for MVD, p < 0.002 for VEGF and p < 0.001 for the other cases). Our results strongly suggest that serum IL-20 concentrations participate actively in the pathophysiology of MM progression. Therefore, it could be used as an indicator of the disease progression and angiogenesis processes.

Bone marrow mast cell density correlates with serum levels of VEGF and CXC chemokines ENA-78 and GRO-α in multiple myeloma.

Angiogenesis is a crucial process in growth and progression of multiple myeloma (MM). Mast cells (MCs) play an important role in MM angiogenesis. Various angiogenic mediators secreted by MCs regulate endothelial cell proliferation and function. Among them, ELR(+) CXC chemokines, such as growth-related oncogen-alpha (GRO-α) and epithelial neutrophil activating protein-78 (ENA-78), have been described as potential mediators in regulation of angiogenesis. The purpose of the study was to quantify MCs in bone marrow (BM) biopsies of MM patients, expressed as MC density (MCD), and correlate it with serum concentrations of vascular endothelial factor (VEGF), GRO-α, ENA-78. Fifty-four newly diagnosed MM patients and 22 healthy controls were studied. Tryptase was used for the immunohistochemical stain of MCs. VEGF, GRO-α, and ENA-78 were measured in sera by ELISA. MCD and serum levels of GRO-α, ENA-78, and VEGF were significantly higher in MM patients compared to controls (p<0.001 in all cases). MCD was significantly increasing with increased stage of the disease (p<0.001). Furthermore, significant correlations were found between MCD with VEGF, GRO-α, and ENA-78. These findings support that MCs participate in the pathophysiology of MM and is implicated in the angiogenic process and disease progression.