The Production of Vascular Endothelial Growth Factor Is Decreased in Acute Myelogenous Leukemia Cases That Are Treated with Chemotherapeutic Agents and Show the Prolonged Bone Marrow Suppression.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4313-4313
Author(s):  
Haruko Tashiro ◽  
Mitsuho Noguchi ◽  
Ryosuke Shirasaki ◽  
Kazuo Kawasugi ◽  
Naoki Shirafuji
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Bone Marrow Cells ◽  
Bone Marrow Suppression ◽  
Myelogenous Leukemia ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Acute Myelogenous ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Objective: There have been reported that the levels of serum vascular endothelial growth factor (VEGF) were decreased in aplastic anemia cases. We investigated VEGF system after chemotherapy to acute myelogenous leukemia (AML) cases, and determined whether VEGF system influenced the prolonged bone marrow suppression in these cases. Materials and Methods: Sera and bone marrow cells were prepared from 30 AML cases including 10 cases of AML (M3) at the onset of the disease, after chemotherapy, and the recovery periods, and the concentration of VEGF in sera of the patients and in the conditioned media obtained from bone marrow-cell cultures was measured with ELISA kit (Quantikine; R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was analyzed with RT-PCR. The biological effect of VEGF on the bone marrow cells which showed the prolonged suppression after chemotherapy was assayed with colony-formation with or without any cytokines. Result and Discussion: As was reported previously, VEGF levels were significantly increased in M3 cases. In other types of AML cases the levels of VEGF production varied. When patients were given chemotherapy and the bone marrow suppression was prolonged, the production levels of VEGF were significantly diminished less than that observed in AML cases with normal bone marrow recovery. In M3 cases that were treated with all-trans retinoic acid and the prolonged bone marrow-suppression was observed, VEGF production was also suppressed. The expression of VEGFR-1 and -2 was observed in bone marrow cells from prolonged bone marrow suppression cases. In these cases, when bone marrow cells were cultured with VEGF, synergistic effects with G-CSF and EPO were observed with colony-formation assay. These observations indicate that VEGF works on the important role for the hematopoietic recovery after chemotherapy in AML cases.

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.

Leukemia-Derived Fibroblast Cells Produce Vascular Endothelial Growth Factor Significantly in Chronic Myelogenous Leukemia Cases.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4544-4544
Author(s):  
Ryosuke Shirasaki ◽  
Haruko Tashiro ◽  
Mitsuho Noguchi ◽  
Kazuo Kawasugi ◽  
Naoki Shirafuji
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Stromal Fibroblast ◽  
Vegf Receptor ◽  
Fibroblast Cells ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Abstract Objective: We reported recently that myofibroblast cells in bone marrow cells of chronic myelogenous leukemia (CML)-patients were partly derived from CML clone, which was identified after long-term bone marrow cell-cultures. The generated BCR-ABL-positive fibroblast cells produced various kinds of cytokines more than that observed in the normal clone-derived fibroblast cells. Among these cytokines, we focus on vascular endothelial growth factor (VEGF)-system in this report. Materials and Methods: Bone marrow cells were collected from chronic myelogenous leukemia cases (20 of chronic phase (CP), 3 of accelerated phase (AP), 8 of blast crisis phase (BC)), which were separated with gravity sedimentation. Obtained non-adherent mononuclear cells were cultured in DMEM with 10% FCS in the humidified 5% CO2 incubator. When cells showed morphological changes into fibroblastoid cells, cells were treated with trypsin and further cultured. The obtained stromal fibroblast cells were sub-cloned into culturing in 96 well plates, and from which RNAs were extracted. cDNAs were synthesized, and RT-PCR was performed to identify BCR-ABL fusion product. The selected clones were further analyzed on DNA levels with FISH to identify BCR-ABL. The concentration of VEGF in the patients’ sera and in the conditioned media of non-adherent mononuclear cells, of fibroblast cells derived from normal clone and of fibroblast cells with BCR-ABL was measured with ELISA kit (R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was also compared at RNA levels. The effect of anti-VEGF antibody to the culturing CML cells was determined using 3H-incorporation assay system. Results and Discussion: The levels of VEGF in sera from CML patients were elevated significantly. However, in patients with CP the expression of VEGF was not observed in non-adherent mononuclear cells. In contrast, VEGF production was observed in non-adherent mononuclear cells from the patients with AP and BC. Stromal fibroblasts produced VEGF in CP, AP and BC, in which BCR-ABL-positive fibroblast cells produced at the significant levels. The expression of VEGFR-1 and -2 was detected in non-adherent mononuclear cells from CP, AP and BC. When non-adherent mononuclear cells from CML patients were cultured onto the stromal fibroblast cells, significant additive effects were observed with 3H-thymidine incorporation assays. And when anti VEGF antibody was added to the cultures, the proliferation activity was significantly decreased. These observations indicate that in CML cases, especially in CP, VEGF plays an important role for the cellular proliferation with paracrine system.

Vascular endothelial growth factor overexpression in myelodysplastic syndrome bone marrow cells: biological and clinical implications

2016 ◽  
Vol 58 (7) ◽  
pp. 1711-1720 ◽  
Author(s):  
Rosangela Invernizzi ◽  
Erica Travaglino ◽  
Matteo Giovanni Della Porta ◽  
Luca Malcovati ◽  
Anna Gallì ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Myelodysplastic Syndrome ◽  
Bone Marrow Cells ◽  
Clinical Implications ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Marrow Cells

scholarly journals Gene Rearrangements in Bone Marrow Cells of Patients with Acute Myelogenous Leukemia

2000 ◽  
Vol 103 (3) ◽  
pp. 125-134 ◽  
Author(s):  
H.M. Schmetzer ◽  
S. Braun ◽  
D. Wiesner ◽  
T. Duell ◽  
H.H. Gerhartz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Gene Rearrangements ◽  
Acute Myelogenous ◽  
Marrow Cells

Induction of nitric oxide by erythropoietin is mediated by the β common receptor and requires interaction with VEGF receptor 2

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 896-905 ◽  
Author(s):  
Larysa Sautina ◽  
Yuri Sautin ◽  
Elaine Beem ◽  
Zhuo Zhou ◽  
Anna Schuler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Common Receptor ◽  
The Common ◽  
Β Receptor ◽  
And Performance ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have profound effects on the endothelium and endothelial progenitor cells (EPCs), which originate from the bone marrow and differentiate into endothelial cells. Both EPO and VEGF have demonstrated an ability to increase the number and performance properties of EPCs. EPC behavior is highly dependent on nitric oxide (NO), and both VEGF and EPO can stimulate intracellular NO. EPO can bind to the homodimeric EPO receptor (EPO-R) and the heterodimeric receptor, EPO-R and the common β receptor (βC-R). Although VEGF has several receptors, VEGF-R2 appears most critical to EPC function. We demonstrate that EPO induction of NO is dependent on the βC-R and VEGF-R2, that VEGF induction of NO is dependent on the expression of the βC-R, and that the βC-R and VEGF-R2 interact. This is the first definitive functional and structural evidence of an interaction between the 2 receptors and has implications for the side effects of EPO.

scholarly journals Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1α

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4258-4263 ◽  
Author(s):  
Keita Kirito ◽  
Norma Fox ◽  
Norio Komatsu ◽  
Kenneth Kaushansky
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is also an important, nonredundant mediator of hematopoietic stem cell (HSC) development. For example, following transplantation, HSC expansion is approximately 15-fold more robust in normal than in Tpo-/- mice. Vascular endothelial growth factor (VEGF) also plays an important role in HSC development, where it acts in an intracellular autocrine fashion to promote cell survival. Thus, we tested the hypothesis that TPO affects the autocrine production of VEGF to account for its favorable effects on HSCs. We found that VEGF transcripts are reduced in purified sca-1+/c-kit+/Gr-1- marrow cells derived from Tpo-/- mice and that TPO induces VEGF transcripts in these primitive hematopoietic cells. Additional studies determined that TPO induces VEGF expression by increasing the level of its primary transcription factor, hypoxia-inducible factor 1α (HIF-1α), by enhancing its protein stability. Moreover, VEGF expression is important for the TPO effect on primitive hematopoietic cells because blockade of the VEGF receptor with a specific inhibitor substantially blunts TPO-induced growth of single sca-1+/c-kit+/Gr-1- marrow cells in serum-free cultures. Along with previous findings that TPO affects Hox transcription factors that regulate HSC proliferation, these data contribute to our growing understanding of the mechanisms by which a hormone can influence stem cell development.

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