Increased Plasma GDF15 Is Associated with Altered Levels of Soluble VEGF Receptors 1 and 2 in Symptomatic Multiple Myeloma

2021 ◽  
pp. 1-8
Author(s):  
Josefin Hidman ◽  
Anders Larsson ◽  
Måns Thulin ◽  
Torbjörn Karlsson
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Correlation Coefficients ◽  
Vascular Endothelial ◽  
Vegf Receptors ◽  
Growth Differentiation Factor 15 ◽  
Pathological Angiogenesis ◽  
Kaplan Meier ◽  
Smouldering Multiple Myeloma ◽  
Endothelial Growth Factor

<b><i>Introduction:</i></b> In multiple myeloma, there is an increase in bone marrow microvascular density and enhanced renal lymphangiogenesis. Increased levels of the proangiogenic protein growth differentiation factor-15 (GDF15) have previously been reported to be associated with poor prognosis in myeloma. A possible association between GDF15 and the soluble forms of vascular endothelial growth factor receptors (sVEGFR) 1 and 2 has not yet been investigated, and a role for these receptors in pathological angiogenesis in myeloma is still to be defined. <b><i>Methods:</i></b> Plasma levels of GDF15 and sVEGFR1 and 2 were determined by ELISA in patients with smouldering multiple myeloma (sMM), patients with symptomatic multiple myeloma (abbreviated as MM), and healthy controls. The levels were compared between the three groups, and correlation coefficients were calculated, as were Kaplan-Meier curves for GDF15 and sVEGFR1 and sVEGFR2. <b><i>Results:</i></b> Levels of GDF15 were significantly higher in MM than in both patients with sMM and controls. A gradual decrease in mean sVEGFR1 concentration was observed, with MM &#x3e; sMM &#x3e; controls. Mean sVEGFR2 was lower in patients with MM than in controls. There was a positive correlation between GDF15 and sVEGFR1, and GDF15 correlated negatively with sVEGFR2. High GDF15 (&#x3e;3 ng/mL) was associated with poor prognosis. <b><i>Conclusion:</i></b> In multiple myeloma, increased expression of GDF15 correlates positively with sVEGFR1 and negatively with sVEGFR2. It is possible that the altered levels of sVEGFR1 and 2 contribute to the increased angio- and lymphangiogenesis observed in myeloma.

Neutralization Of Vascular Endothelial Growth Factor-A Induced CD138-Expression In Bone Marrow Cells From Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5331-5331
Author(s):  
Ryosuke Shirasaki ◽  
Takuji Matsuo ◽  
Yoko Oka ◽  
Jun Ooi ◽  
Naoki Shirafuji
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Poor Prognosis ◽  
Bone Marrow Cells ◽  
Vascular Endothelial ◽  
Normal Individuals ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Background We previously reported that when adult human dermal fibroblasts were cultured with interleukin (IL)-1-b, vascular endothelial growth factor (VEGF)-A was produced significantly (54th ASH). And, when antihuman VEGF-A neutralizing antibody (VEGF-A Ab) was added to the cultures, CD138 (Syndecan-1) expressed significantly. CD138 is a member of cell-surface transmembrane haparan sulfate proteoglycans, and expresses in plasma cells from multiple myeloma (MM) cases. Membrane-anchoring CD138 shows a better prognosis in an immunodeficiency murine transplantation model in vivo; however, when extra-domain of CD138 is digested by heparanase to be shed from the cell-surface, MM cells invade to various kinds of tissues, and the patients show poor prognosis. Aims To validate a biological implication of inhibition of VEGF-A-signaling in MM cells, we observed effects of VEGF-A Ab to bone marrow cells from MM patients. Cell-proliferations as well as morphological changes were also observed time-dependently. Materials and Methods Institutional ethical committee approved our study, and bone marrow cells were obtained from the informed MM patients as well as normal individuals. Cells were separated with gravity-sedimentation method, and the prepared mononuclear cells were cultured with or without VEGF-A Ab, and the expression of specific genes was analyzed. Results Twenty MM patients were eligible, in which three showed significant poor prognosis, and worsened after underwent intensive chemotherapy or allogeneic hematopoietic stem cells transplantation. Thirteen out of twenty expressed CD138, and when cells were cultured with VEGF-A Ab for four days, CD138-expression increased significantly in all cases. Four did not express CD138; however, CD138-expression was observed after 4 day’s culture with VEGF-A Ab. In three progressed cases CD138-expression decreased in accordance with the disease-progression; however, when VEGF-A Ab was added to the cell-cultures, CD138 was induced to express. Heparanase-expression was observed in 10 cases out of 20, which were down-regulated when VEGF-A Ab was added to the cultures. In contrast, in bone marrow cells from seven normal individuals CD138-expression was very low, which was down-regulated with the addition of VEGF-A Ab. Heparanase-expression was not observed in these normal cells, and were induced to be observed in four out of seven when VEGF-A Ab was added to the cultures. Discussion Expression of CD138 is induced in fibroblast by the addition of fibroblast growth factor-2, and in keratinocytes by epidermal growth factor and keratinocyte growth factor; however, an induction of CD138 by the VEGF-A Ab has not been reported. Several cytokines including VEGF-A influence plasma cell-proliferation; however, little is reported on cytokine-suppression therapy. Inhibition of the signaling of VEGF receptors by the chemicals including solafenib is not specific for VEGF-A. Currently we validate the efficacy of the inhibition of VEGF-A-signaling to MM cells and their environmental cells using RNA interference. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The VAD Scheme versus Thalidomide plus VAD for Reduction of Vascular Endothelial Growth Factor in Multiple Myeloma: A Meta-Analysis

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Gan-Lin He ◽  
Duo-Rong Xu ◽  
Wai-Yi Zou ◽  
Sui-Zhi He ◽  
Juan Li
Keyword(s):  
Multiple Myeloma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Meta Analysis ◽  
Biomedical Literature ◽  
Cochrane Library ◽  
Vascular Endothelial ◽  
China National Knowledge Infrastructure ◽  
Significant Difference ◽  
Endothelial Growth Factor

The VAD (vincristine-doxorubicin-dexamethasone) regimen has been used for decades to treat multiple myeloma (MM). Based on reports that vascular endothelial growth factor- (VEGF-) mediated angiogenesis is critical for MM pathogenesis, the antiangiogenic compound thalidomide has been added to VAD (T-VAD). However, it remains unclear whether T-VAD is more efficacious than VAD for serum VEGF reduction or if the difference influences clinical outcome. Pubmed, Cochrane library, China Biomedical Literature (CBM) database, China National Knowledge Infrastructure (CNKI) database, Vip database, and Wanfang database were searched for relevant studies published up to June 2017. RevMan5.2 was used for methodological quality evaluation and data extraction. Thirteen trials (five randomized, seven nonrandomized, and one historically controlled) involving 815 cases were included. Serum VEGF was significantly higher in MM cases than non-MM controls (MD=353.01, [95%CI 187.52–518.51], P<0.01), and the overall efficacy of T-VAD was higher than that of VAD (RR=1.36, [1.21–1.53], P <0.01). Further, T-VAD reduced VEGF to a greater extent than VAD does ([MD=-49.85, [-66.28− -33.42], P<0.01). The T-VAD regimen also reduced VEGF to a greater extent in newly diagnosed MM patients than it did in recurrent patients ([MD=-120.20, [-164.60–-39.80], P<0.01). There was no significant difference in VEGF between T-VAD patients (2 courses) and nontumor controls (MD=175.94, [-26.08–377.95], P=0.09). Greater serum VEGF reduction may be responsible for the superior efficacy of T-VAD compared to VAD.

scholarly journals Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology

2018 ◽  
Vol 11 (552) ◽  
pp. eaau1165 ◽  
Author(s):  
Ameer L. Elaimy ◽  
Arthur M. Mercurio
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Vascular Endothelial ◽  
Vascular Growth ◽  
Vegf Signaling ◽  
Pathological Angiogenesis ◽  
Cytoskeletal Dynamics ◽  
Rho Family ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) stimulates endothelial cells to promote both developmental and pathological angiogenesis. VEGF also directly affects tumor cells and is associated with the initiation, progression, and recurrence of tumors, as well as the emergence and maintenance of cancer stem cells (CSCs). Studies have uncovered the importance of the transcriptional regulators YAP and TAZ in mediating VEGF signaling. For example, VEGF stimulates the GTPase activity of Rho family members and thereby alters cytoskeletal dynamics, which contributes to the activation of YAP and TAZ. In turn, YAP- and TAZ-mediated changes in gene expression sustain Rho family member activity and cytoskeletal effects to promote both vascular growth and remodeling in endothelial cells and the acquisition of stem-like traits in tumor cells. In this Review, we discuss how these findings further explain the pathophysiological roles of VEGF and YAP/TAZ, identify their connections to other receptor-mediated pathways, and reveal ways of therapeutically targeting their convergent signals in patients.

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