The role of nuclear factor kappaB on angiogenesis regulation through monocyte chemotactic protein-1 in myeloma.
Multiple myeloma is malignant proliferation of plasma cells and plasmacytoid cells. Vascular endothelial growth factor (VEGF) is known to be one of the most important if not the main regulator of physiologic and pathologic angiogenesis which triggers growth, survival and migration of myeloma cells. It has been shown that circulating mature or bone marrow driven endothelial precursor cells play an important role in neovascularisation. In accordance with these observations, current therapeutic approaches to myeloma include VEGF inhibitors. Since angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes many products with a different function it would be of benefit to determine the key molecule produced by transformed plasma cells which stimulates bone marrow environment to produce their homing "milieu" secreting different cytokines such as VEGF, IL-6, and monocyte chemotactic protein-1 (MCP-1). This molecule could be nuclear factor kappa B (NF-kappaB). It has been confirmed that myeloma cells express and produce NF-kappaB. It has been established recently that by blocking NF-kappaB production MCP-1 secretion is reduced up to 60%. If so, this would also reduce production of IL-6 and VEGF, since MCP-1 upregulates VEGF and IL-6 production. This way one could make bone marrow bad environment for myeloma cells to settle, followed with no disease progression. Targeting to NF-kappaB intended to inhibits its activation with receptor antagonist would possibly significantly inhibit lipopolysaccharide-induced IL-6, MCP-1 and TNF-alpha. All of them being stimulators for VEGF secretion and indirectly activation of angiogenesis. To conclude, angiogenesis could be induced by myeloma cells themselves through NF-kappaB activation pathway and by inhibiting its activation we might prevent myeloma expansion in bone marrow and progression of the disease by decreased MCP-1 secretion.
Stifter
Sanja
S
Pathology Department, School of medicine, Braće Branchetta 20, 51000 Rijeka, Croatia. sstifter@medri.hr
D018932:Chemokine CCL2 / Q000502:physiology*; D006801:Humans; D009101:Multiple Myeloma / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology*; D009389:Neovascularization, Pathologic
D018932:Chemokine CCL2; D016328:NF-kappa B