| Abstract |
Background: Multiple myeloma is an incurable malignancy of plasma cells, developed at the bone marrow. In order to settle and then expand, myeloma plasma cells interact with the elements of the bone microenvironment, which is being transformed. Angiogenesis, ie the formation of new blood vessels from the pre-existing ones, being involved in tumor development, is dependent on these interactions. There is already enough information on the process of angiogenesis, in multiple myeloma as well as in other malignancies, that has created models of therapeutic interventions. Already used regimens, based on angiogenesis among others, have shown significant efficacy, especially in myeloma tumors. Nevertheless, the disease remains incurable and therefore the comprehension of the involved mechanisms in the biology of myeloma progression is necessary.
Aim: The aim of the current study was to examine the role of various angiogenic molecules in progression of multiple myeloma. In order to achieve this, the peripheral expression of various molecules with potential angiogenic activity was measured. Furthermore, the relationship of this expression, with the angiogenic activity of bone marrow, the proliferative activity of malignant plasma cells and the burden of disease, was also examined.
Material & Methods: We studied 65 myeloma patients in diagnosis, and 40 of them who responded to treatment. We also studied 25persons with MGUS and 30 controls. The study was performed in 4 independent stages. In the first stage, we measured serum levels of the angiogenic marker sCD105, together with its ligand TGF-β1 and bone marrow angiogenic activity, estimated by microvascular density (MVD) and disease activity, estimated by serum levels of IL-6 and bone marrow expression of of Ki-67 PI. In the second stage we measured serum levels of sCD40L, in combination with known angiogenic factors, HGF and VEGF, and markers of disease activity, (by measuring serum levels of IL-6 and bone marrow plasma cell infiltration and expression of Ki-67 PI). In the third stage, we measured serum levels of the angiogenic marker PDGF-AB, together with bone marrow MVD and serum levels of ANG, bFGF, IL-6, LDH and B2M. In the fourth stage, we assessed serum levels of disease activity indices MIP-α, IL-1β, LDH and indirect angiogenic molecules IL-8 and IL-6, in combination with bone marrow proliferation marker PCNA. The measurement of cytokines in serum was performed by ELISA method, whereas the
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expressions of Ki-67, PCNA and MVD in the bone marrow were evaluated immunohistochemically.
Results: Serum levels of sCD105, sCD40L, PDGF-AB, IL-6, IL-8, IL-1β and MIP-1α, as well MVD and bone marrow expression of Ki-67 PI and PCNA, were increased in patients compared to controls, and were in parallel with progress of the disease stage. Furthermore, their values decreased significantly after effective treatment. sCD105 correlated with MVD, IL-6 and the expression of Ki-67PI, sCD40L correlated with HGF, VEGF, IL-6 and expression of Ki-67PI and PDGF-AB correlated with b-FGF, ANG, IL-6, B2M and MVD. Finally, expression of PCNA correlated with the measured cytokines. Moreover, IL-6 correlated with IL-8, IL-1β and MIP-1α, IL-8 and MIP-1α with B2M and LDH, while the values of B2M and IL-1β were found to independent prognostic indices.
Conclusions: Serum levels of sCD105, sCD40L and PDGF-AB are elevated in patients with multiple myeloma and associated with the burden of disease (stage, cytokines, response to treatment), the proliferative potential of plasma cells (Ki-67 expression and PCNA) and the angiogenic process (microvessel density, angiogenic cytokines). Therefore, the correlation of those angiogenic mediators with indices of disease activity, suggests the significant contribution of angiogenesis in the complex mechanisms induced by myeloma cell disease in the bone microenvironment. This notion could be useful, since the studied cytokines could be useful both for prognostic purposes and for designing models for new therapeutic interventions.
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Ο ρόλος του CD105, CD40-ligand και άλλων αγγειογενετικών κυτταροκινών στην ανάπτυξη του πολλαπλού μυελώματος
