multiple myeloma ( mm ) is a clonal b - cell dyscrasia characterized by the accumulation of monotypic paraprotein - secreting cells in the bone marrow ( bm ) , in close contact with adjacent cells in its microenvironment . a recent study reported that angiogenesis plays a significant role in the pathogenesis of mm . plasma cells secrete a well - known angiogenic cytokine , vascular endothelial growth factor ( vegf ) , in response to stimulation of inflammatory factors , such as interleukin ( il)-6 , il-10 , il-17 , and il-20 [ 47 ] ; on the other hand , microvascular endothelial cells ( ecs ) and bm stromal cells secrete other potent growth factors for malignant plasma cells , thus regulating vegf stimulation . another angiogenic cytokine , angiopoietin-2 ( ang-2 ) , prevents tie-2 binding and leads to vessel instability , associated with sprouting angiogenesis . these accumulated data suggest that angiogenesis is tightly controlled by angiogenic cytokines and inflammatory factors in mm . il-37 protein is associated with plasma cells and constitutively expressed in the cytoplasm of monocytes and peripheral blood mononuclear cells . il-37 was reported to markedly inhibit the migration and proliferation and promote apoptosis in renal cell carcinoma . moreover , il-37 prevented the pathogenesis of malignant b - cell neoplasms and nrasv12-mediated oncogenesis . the aim of this study was to measure serum levels of il-37 in patients in different stages of mm and to correlate these levels with vegf and ang-2 in order to investigate their clinical significance . the original research was approved by the medical ethics committee of our hospital , and every patient provided written informed consent . we excluded individuals with hypertension , those with diabetes , and those who received any other surgery . the stage of mm was classified according to the international staging system ( iss ) . all participants in this study were from binzhou people s hospital ( china ) , since january 2011 . all blood samples were collected , mixed with edta , centrifuged at 3000 rpm for 15 min at room temperature , then stored at 80c and analyzed at the end of the collection . the detection of il-37 , vegf , and ang-2 in the serum was performed by elisa ( r&d systems , ca , usa ) , according to the operating manual . the tube formation of vascular - like structures was determined by human umbilical vein ecs ( huvecs ) on matrigel ( bd biosciences , franklin , nj , usa ) . onto a 48-well plate coated with 150 l matrigel , 410 huvecs were planted . cells were treated with recombinant human il-37 ( rhil-37 ; 100 ng / ml ) or phosphate buffer solution and then were maintained at 37c , 5% co2 , for 6 h. tubes were defined as straight cellular extensions joining 2 cell masses ; 3 random digital images ( 200 ) were counted for each well . one - way analysis of variance , followed by t test , was used to examine differences between stages . the original research was approved by the medical ethics committee of our hospital , and every patient provided written informed consent . we excluded individuals with hypertension , those with diabetes , and those who received any other surgery . the stage of mm was classified according to the international staging system ( iss ) . all participants in this study were from binzhou people s hospital ( china ) , since january 2011 . all blood samples were collected , mixed with edta , centrifuged at 3000 rpm for 15 min at room temperature , then stored at 80c and analyzed at the end of the collection . the detection of il-37 , vegf , and ang-2 in the serum was performed by elisa ( r&d systems , ca , usa ) , according to the operating manual . the tube formation of vascular - like structures was determined by human umbilical vein ecs ( huvecs ) on matrigel ( bd biosciences , franklin , nj , usa ) . onto a 48-well plate coated with 150 l matrigel cells were treated with recombinant human il-37 ( rhil-37 ; 100 ng / ml ) or phosphate buffer solution and then were maintained at 37c , 5% co2 , for 6 h. tubes were defined as straight cellular extensions joining 2 cell masses ; 3 random digital images ( 200 ) were counted for each well . one - way analysis of variance , followed by t test , was used to examine differences between stages . serum levels of il-37 decreased in active patients with mm compared with healthy control subjects , whereas vegf and ang-2 increased , as shown in table 2 . table 3 shows the values in each iss stage ; it also shows that vegf and ang-2 increased and il-37 decreased in parallel with disease stage ( p<0.001 for all cases ) . significant negative correlations were found between serum levels of il-37 with vegf ( r=0.337 ; figure 1 ) and ang-2 ( r=0.306 ; p<0.05 ; figure 2 ) , and a positive correlation was found between vegf and ang-2 ( r=0.6458 ; p<0.001 ; figure 3 ) . compared with the control ( 1.000.24 ) , rhil-37 pretreatment significantly decreased tube formation in huvecs ( 0.670.12 ) and significantly reduced supernatant vegf levels in huvecs ( figure 3c ) . more and more evidence indicates that bm angiogenesis is crucial to mm pathogenesis and that the angiogenic and antiangiogenic switch contributes to mm progression . the identification and specific contribution of proangiogenic molecules to be used as therapeutic targets and/or reliable angiogenesis biomarkers in mm is still unresolved . in this article , we show that il-37 correlates significantly with important angiogenetic factors , suggesting that il-37 may be a biomarker for mm disease stage and angiogenesis processes . we first determined serum il-37 , vegf , and ang-2 levels in patients with mm at different stages of disease and in healthy control subjects . we found that , compared with healthy control subjects , serum levels of il-37 decreased in patients with mm , whereas vegf and ang-2 levels increased , depending on iss stage . these data support a putative value of these molecules in the mm disease process . il-37 is a newly identified member of the il-1 family , which are proinflammatory cytokines demonstrating various anti - inflammatory and immunosuppressive properties in response to infection and inflammation . recently , il-37 emerged as a fundamental anti - inflammatory cytokine , favoring tumor escape from immune surveillance . high expression of il-37 , which may mediate antitumor immunity by regulating natural killer cell activity , was associated with better overall survival in hepatocellular carcinoma . the ectopic selection of il-37 preserved the function of b - cell progenitors and prevented nrasv12-mediated oncogenesis in aging . these results all suggest the essential role played by il-37 in the tumor microenvironment . through this research , we verified that serum il-37 levels in patients with mm were lower than in healthy control subjects and that levels decreased with advancing disease . upon activation by mm plasma cells and mesenchymal stromal cells , macrophages can release growth factors , proteolytic enzymes , cytokines , and inflammatory mediators that promote plasma cell growth and survival . indeed , these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry , and this ability proceeds in step with progression of the plasma cell tumors . observed reduced systemic levels of il-10 and local interferon - gamma gene transcripts in keratin-14 vegf - a transgenic mice treated with plasmid coding human il-37 sequence - formulated cationic liposomes . in mm , plasma cells secrete various angiogenic cytokines , such as vegf , matrix metalloproteinase-2 , and fibroblast growth factor-2 , which in turn cause inflammatory cells to secrete other angiogenic factors . all these factors enlist and activate mm - associated macrophages to cooperate with other cells in angiogenesis . bm sera with high ang-2 levels specifically contributed to ec activation , suggesting that ang-2 produced in the bm may contribute to mm angiogenesis . in our study , we found that both vegf and ang-2 were significantly higher in patients with mm than in healthy control subjects and that these values increased in parallel with disease progression . we also confirmed elevated il-37 levels in mm significant negative correlations with vegf and ang-2 . in view of these facts , we further investigated whether angiogenesis could be weakened by the increased expression of il-37 . we found that the tube formation of huvecs , which was also suppressed by rhil-37 pretreatment , may be involved in vegf secretion . these results suggest that il-37 may play an important role in angiogenesis during mm progression . our results show that in patients with mm , serum vegf and ang-2 levels increase and il-37 level decreases with disease progression . these results suggest that serum levels of il-37 play a part in the pathophysiology of mm progression . therefore , il-37 could serve as a biomarker of the disease state and angiogenesis processes in mm .