Levels of angiogenic factors in patients with multiple myeloma correlate with treatment response

Abstract

Angiogenesis plays a significant role in the pathogenesis of multiple myeloma (MM). We have measured concentrations of angiogenesis activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hepatocyte growth factor (HGF), and inhibitors, including endostatin, thrombospondin-1 (TSP-1), and angiostatin in the peripheral and bone marrow blood of MM patients at diagnosis and after high-dose chemotherapy. We have analyzed 96 patients with secretory MM. Serial measurements of angiogenesis factors/inhibitors were analyzed in the plasma by subgroups based on the best treatment response. Concentrations of angiogenic factors were determined in the peripheral blood and bone marrow plasma. There were significant decreases of VEGF and HGF levels and a significant increase in TSP-1 concentrations in the bone marrow plasma of patients who achieved complete or very good partial response in contrast to those who had partial or no response. VEGF and HGF levels decrease but those of TSP-1 increase after successful treatment for MM, indicating a reduction in the rate of angiogenesis.

Predictive and Prognostic Significance of Vascular Endothelial Growth Factor (VEGF) and Response to VAD Protocol of Chemotherapy In Multiple Myeloma Patients

“…In multiple myeloma, vascular endothelial growth factor was produced by malignant plasma cells and stimulates the proliferation of endothelial cells, also at the same time, vascular endothelial growth factor had secreted by endothelial cells in the tumor microenvironment it acted in an autocrine and paracrine way on both endothelial and myeloma cells, so there was a reciprocal stimulation between endothelial cells and myeloma cells to produce it [12] . A significant increment in plasma level of vascular endothelial growth factor and its soluble receptor -2 in myeloma patients at diagnosis before starting chemotherapy protocol with significant decrement in there plasma levels after four courses of VAD protocol of therapy in responded patients and this was consistent with same data observed by Mileskhin et al who reported that high levels of vascular endothelial growth factor were associated with response rate in patients treated chemotherapy [13,16] . Anther contradictory results were detected by Cibeira and collaborators who noticed that there was not a significant correlation between response rate and vascular endothelial growth factor level or its receptor-2 [14,15] and this might attributed to different in selection criteria of patients or method of assessment as the concentrations of angiogenesis factors in the plasma rather than in the serum because platelets contain significant concentrations of these cytokines, released during during preparation of serum [6,17] .…”

“…Anther contradictory results were detected by Cibeira and collaborators who noticed that there was not a significant correlation between response rate and vascular endothelial growth factor level or its receptor-2 [14,15] and this might attributed to different in selection criteria of patients or method of assessment as the concentrations of angiogenesis factors in the plasma rather than in the serum because platelets contain significant concentrations of these cytokines, released during during preparation of serum [6,17] . Vascular endothelial growth factor and its soluble receptor -2 in myeloma patients had associated with other poor prognostic factors and both of them had independent risk factors with a predictive value due to significant decrement in there plasma level after four courses of VAD protocol of therapy in responded patients reflecting decrement of angiogenesis rate in myeloma patients after therapy [16] . The aim of front-line therapy for multiple myeloma was to substantially decrease tumor burden and the degree of disease Variables VEGF(pg/mL) Before Therapy After Therapy P value VEGFR-2(ng/mL) Before Therapy After Therapy P value Variables albumin<3.5 g/dL β2microglobulin ≥5.5μg/mL Creatinine ≥2 mg/dL VEGF (pg/mL) at diagnosis ≥40 VEGFR-2 (ng/mL) at diagnosis ≥10 reduction is associated with improved outcome, including prolonged progression-free survival (PFS) and overall survival (OS) [17] .…”

Widespread Deregulation of Phosphorylation-Based Signaling Pathways in Multiple Myeloma Cells: Opportunities for Therapeutic Intervention

“…Hypoxic factors such as NO are capable inducers of angiogenesis, and NO signaling through PKG has been linked to insulin-induced production of vascular endothelial growth factor (VEGF-1) in smooth muscle cells (24). This potent angiogenic factor is also secreted by MM cells in response to IGF-1 stimulation, and increased VEGF-1 serum levels are correlated with poor prognosis in MM patients (25,26). Interestingly, malignant MM PC express high levels of nitrotyrosine, a marker of NO presence, and NOsynthase 1, 2 and 3.…”

Phase IB study of cabozantinib in patients with relapsed and/or refractory multiple myeloma

“…Multiple therapies targeting either the CNS or CLL have been used with variable results in terms of rate and duration of response. 4,5 Outcome after CNS treatment is not established and controversies persist about the need to control the systemic CLL.…”

“…1 HGF and HGF receptor protein (MET) have been implicated in myeloma pathogenesis based on the observation that elevated HGF levels are associated with worse prognosis [2][3][4] and lack of response to chemotherapy. 5,6 In addition, MM cells express HGF, creating a putative autocrine HGF/MET loop. [7][8][9] In vitro models demonstrated myeloma cell growth inhibition through MET or HGF inhibition.…”