ORIGINAL PAPER Serum concentrations and clinical significance of soluble CD40 ligand in patients with multiple myeloma G. Tsirakis • C. A. Pappa • F. E. Psarakis • M. Fragioudaki • C. Tsioutis • E. Stavroulaki • A. Boula • M. G. Alexandrakis Received: 14 September 2011 / Accepted: 23 February 2012 Ó Springer Science+Business Media, LLC 2012 Abstract Multiple myeloma (MM) is a disease of plasma cells that express the CD40 receptor. Binding of the CD40 by its natural ligand, CD40 ligand (CD40L), produces growth arrest and/or apoptosis in MM. To evaluate serum levels of soluble CD40L (sCD40L) in MM patients and to correlate them with markers of disease activity and angi- ogenesis, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-6 (IL-6), proliferation marker Ki-67 proliferation index (Ki-67 PI) and bone marrow plasma cell infiltration, fifty- eight MM patients were studied in diagnosis and 43 of them after completion of treatment. Serum levels of sCD40L, VEGF, HGF and IL-6 were measured by ELISA, whereas Ki-67 PI and bone marrow plasma cell infiltration were measured by immunohistochemistry. Pre-treatment levels of sCD40L in MM patients were higher compared to controls and to their levels after effective treatment. Treatment reg- imen did not affect the degree of reduction of sCD40L levels, whereas patient in partial remission had increased levels compared to those with better response. Significant differ- ences were found among disease stages. There were also positive correlations between CD40L with HGF, VEGF, IL- 6 and Ki-67 PI. Elevated serum sCD40L is found in patients with advanced MM stage and can be reduced after effective treatment. Increased levels of this mediator are correlated with angiogenic cytokines, providing evidences that CD40L/ CD40 interactions play a significant role in the mechanisms of angiogenesis in MM patients. Keywords CD40L Á Cytokines Á Multiple myeloma Á Angiogenesis Introduction Multiple myeloma (MM) is a B-cell malignancy charac- terized by the clonal proliferation and accumulation of malignant plasma cells in the bone marrow (BM) [1]. The process of tumorigenesis in MM includes the expression of genes controlling cell cycle progression. CD40 ligand (CD40L, also called CD154) is a 33-kD type II membrane-protein, member of the TNF family, is the natural ligand for CD40 and is predominantly expressed by activated CD4 ? T cells and platelets [2, 3], although it is also expressed on many other cell types [4, 5]. Interactions between CD40L and CD40 have been reported to have sig- nificant role in the mechanisms for cytotoxicity against CD40- expressing tumors and for the regulation of immune response [6–8]. As reported previously, many hemopoietic malignan- cies express, in their cellular membranes, CD40 and undergo a range of cellular changes in response to CD40 ligation [9, 10]. These cellular changes can either increase or decrease malignant cell growth according to the cell type [11, 12]. CD40 is commonly expressed on human MM cells [7, 13] but not on normal, terminally differentiated plasma cells [7, 9]. Recently, it was reported that binding of the CD40 receptor by its natural ligand, CD40L, produces growth arrest and/or apoptosis in MM as well as in other B-cell malignancies [9, 13]. CD40L plays also a significant role in the activation of antigen-presenting cells as dendritic cells [14, 15]. It is char- acterized also as a costimulatory agent inducing the increased G. Tsirakis (&) Á M. Fragioudaki Á C. Tsioutis Á M. G. Alexandrakis Haematology Department, University Hospital of Heraklion, Heraklion, Crete, Greece e-mail: Georgetsirakis@gmail.com C. A. Pappa Á F. E. Psarakis Á E. Stavroulaki Á A. Boula Haematology Department, Venizelion General Hospital of Heraklion, Heraklion, Crete, Greece 123 Med Oncol DOI 10.1007/s12032-012-0203-2