scholarly journals The Association Between Vascular Endothelial Growth Factor (VEGF) Levels And Prognosis In Patients Chronic Lymphocytic Leukemia

2020 ◽  
Vol 9 (1) ◽  
pp. 1-9
Author(s):  
Esra Terzi Demirsoy ◽  
Muhlis Cem Ar
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Uncovering Thalidomide Mechanism of Action: Neuropilin 1 Represents the Target of Antiangiogenic and Immunomodulatory Effect in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4608-4608
Author(s):  
Krzysztof Giannopoulos ◽  
Marcin Omiotek ◽  
Kamila Kosior ◽  
Radoslaw Mlak ◽  
Malgorzata Kowal ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Mechanism Of Action ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor ◽  
Median Expression

Abstract Abstract 4608 In chronic lymphocytic leukemia (CLL) thalidomide was found to significantly decrease the percentage of regulatory T cells (Tregs) as well the number of CLL cells in vivo. In combination with fludarabine, thalidomide was effective both in refractory/relapse and naïve CLL patients. In our recent clinical trial, we also observed a reduction of vascular endothelial growth factor (VEGF) levels during therapy that were correlated with the reduction of Tregs (r2=0.47, p<0.05). Furthermore, gene expression profiles associated with thalidomide response in CLL revealed several genes involved in angiogenesis (Giannopoulos et al. Leukemia 2009). To further characterize the thalidomide mechanism of action in CLL we assessed expression of neuropilin 1 (NRP1), which is a membrane-bound coreceptor to the tyrosine kinase receptor for both vascular endothelial growth factor (VEGF) and semaphorin (SEMA3A) family members. NRP1 plays versatile roles in angiogenesis, cell survival, migration, and invasion. Recently, NRP1 was also found expressed on plasmacytoid dendritic cells (PDC) as well as on Tregs, two immune cell subpopulations involved in tolerance mechanisms commonly deregulated in tumorigenesis. Our analysis showed NRP1 expression on CLL cells, Tregs and PDC of 38 CLL patients. Using five parameter flow cytometry we found increased expression of NRP1 in CLL when compared to cells derived from healthy volunteers. NRP1 expression was 22.7% on CD5+CD19+ CLL cells vs. 6.2% on CD19+ B cells from controls, p=0.03. Furthermore, we found expression of NRP1 on Tregs as well as PDC with a median expression of NRP1 on Tregs of 42.6 % (range: 10 – 100%). NRP1 was expressed on almost all PDC with a median expression of 100% (range: 98.2 – 100%). In functional studies, we found that NRP1 expression might be regulated by VEGF expression levels. Magnetically separated CLL cells increased expression of NRP1 after cell culture with VEGF. Here, VEGF levels of 0.1 – 0.5ng/ml, which are also observed in primary CLL patient samples, effectively induced expression of NRP1. In accordance, we also observed that VEGF upregulates NRP1 expression on magnetically separated Tregs. However, higher VEGF concentrations inhibited NRP1 expression in CLL cells probably due to a negative feedback loop. In conclusion, we found expression of NRP1 on CLL cells, Tregs as well as PDC in patients with CLL, and we could demonstrate that the expression of NRP1 is regulated by VEGF expression levels. Thus, our previously observed thalidomide-induced reduction of VEGF levels along with a reduced percentage of Tregs in CLL might in part be explained by down-regulation of the NRP1 expression. Disclosures: Stilgenbauer: Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel Grants.

Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 768-770 ◽  
Author(s):  
Alvaro Aguayo ◽  
Susan O'Brien ◽  
Michael Keating ◽  
Taghi Manshouri ◽  
Cristi Gidel ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Early Stage Disease ◽  
Normal Peripheral Blood ◽  
Endothelial Growth Factor ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Strong evidence exists for an association between high vascular endothelial growth factor (VEGF) levels and poor prognoses in patients with solid tumors and acute leukemia. Using Western blot analysis and solid-phase radioimmunoassay, we measured cellular VEGF levels in B-cell chronic lymphocytic leukemia (CLL) samples from 225 patients and correlated these levels with disease characteristics and prognoses. The median VEGF level in CLL samples was 7.26 times the median level detected in normal peripheral blood mononuclear cells. Patients with lower levels of VEGF protein showed a trend toward shorter survival (P = .07). However, in a subgroup of CLL patients with good prognoses or early-stage disease (Rai stages 0-II, Binet stages A,B; β2-M ≤ 2.8 mg/dL), lower levels of VEGF were associated with shorter survival times. For the entire group of patients, no correlation was found between VEGF levels and β2-M levels or Rai and Binet stage. Most samples from patients with CLL expressed the 43-kd VEGF isoform in addition to the commonly expressed 45-kd isoform. It remains to be seen whether the expression of the 43-kd isoform is responsible for this reversed correlation with outcome.

Clinical Relevance of Vascular Endothelial Growth Factor Type A (VEGFA) and VEGF Receptor Type 2 (VEGFR2) Gene Polymorphism In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4467-4467
Author(s):  
Joanna Gora-Tybor ◽  
Krzysztof Jamroziak ◽  
Zofia Szemraj ◽  
Janusz Szemraj ◽  
Ewa Lech-Maranda ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Allele Frequencies ◽  
Vascular Endothelial ◽  
Factor Type ◽  
Endothelial Growth Factor

Abstract Abstract 4467 Vascular endothelial growth factor type A (VEGFA) is a key regulator of angiogenesis and vascular permeability. Given that chronic lymphocytic leukemia (CLL) cells secrete VEGFA, express VEGFA receptors and circulate in blood with increased VEGFA level it is likely that VEGFA-mediated signaling may influence CLL clone survival. In this case-control study we verified the hypothesis that inherited differences in activities of VEGFA and its main receptor in CLL, vascular endothelial growth factor receptor type 2 (VEGFR2, also known as kinase insert domain-containing receptor/fetal liver kinase-1, Flk/1/KDR) impact predisposition to CLL or the course of the disease. Four functional single nucleotide polymorphisms (SNPs) including two SNPs in VEGFA gene, namely +405G>C (rs2010963) and +936C>T (rs3025039) and two SNPs in VEGFR2 gene, namely -271G>A and +1719A>T (rs1870377) were genotyped using PCR-based assays in 175 Caucasian CLL patients and 133 ethnically, geographically, age and sex matched controls. The minor allele frequencies in CLL patients were found as follows: 0.36 for +405C VEGFA allele, 0.17 for +936T VEGFA allele, 0.46 for -271 VEGFR2 allele and 0.35 for +1719A VEGFR2 allele. The genotype and allele frequencies of all tested SNPS in VEGFA and VEGFR2 genes did not differ significantly between cases and controls (p>0.05). No genotype or allele was significantly associated with important prognostic factors in CLL including clinical stage, IgVH mutational status, ZAP-70 expression and FISH cytogenetic abnormalities. Furthermore, the carriers of different VEGFA and VEGFR2 genetic variants had comparable time to CLL treatment initiation. In conclusion, the results of our study do not support major involvement of genetic polymorphisms in VEGFA mediated pathway in susceptibility to CLL or its outcome. Disclosures: Robak: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding.

In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3181-3187 ◽  
Author(s):  
Haijuan Chen ◽  
Andy T. Treweeke ◽  
Dave C. West ◽  
Kathleen J. Till ◽  
John C. Cawley ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Culture Media ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Vegf Protein

Expansion of primary solid tumors and their malignant dissemination are angiogenesis-dependent. Vascular endothelial growth factor (VEGF) is the key factor playing a pivotal role in solid tumor-induced angiogenesis. Recent studies indicate that angiogenesis may also be involved in the pathogenesis of certain hemic malignancies, including B-cell chronic lymphocytic leukemia (B-CLL). Mechanisms underlying angiogenesis in B-CLL and the role of VEGF in this process are incompletely understood. In this study, it was examined whether angiogenically functional VEGF is produced by B-CLL cells. Immunohistochemical staining with antibodies against VEGF and CD34, an endothelial cell marker, demonstrated the presence of VEGF protein and abundant blood vessels in infiltrated lymphoreticular tissues. Low levels of VEGF were detected by ELISA in the culture media of unstimulated cells; this was enhanced up to 7-fold by hypoxic stimulation. SDS-PAGE and Western blot analysis of the concentrated culture media showed 2 isoforms of VEGF protein with molecular weights of 28 and 42 kd, respectively. RNA hybridization showed that these cells expressed VEGF mRNA. Reverse transcription–polymerase chain reaction, combined with nucleotide sequence analysis, revealed that the predominantly expressed isoforms were VEGF121 and VEGF165. Moreover, 3H-thymidine incorporation and an in vivo angiogenic assay demonstrated that the VEGF produced by CLL cells can induce angiogenesis by stimulating endothelial cell proliferation. In conclusion, this study shows that B-CLL cells produce VEGF and demonstrates the angiogenic effects of this growth factor, which may be relevant for the tissue phase of the disease.

The Vascular Endothelial Growth Factor (VEGF) Autocrine Survival Signaling Pathway in Chronic Lymphocytic Leukemia (CLL) Is Regulated by Lysophosphatidic Acid (LPA).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2810-2810
Author(s):  
Xiaojie Hu ◽  
Jinmie Sun ◽  
James B. Johnston ◽  
Spencer B. Gibson
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Protective Effect ◽  
Receptor Activation ◽  
Lymphocytic Leukemia ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Receptor Inhibitor

Abstract Vascular endothelial growth factor (VEGF) is a survival and angiogenesis factor that has been the target of chemotherapy in a variety of cancers including chronic lymphocytic leukemia (CLL). The VEGF survival response is regulated by an autocrine loop where cells constitutively express VEGF and activate the VEGF receptors leading to up-regulation of anti-apoptotic Bcl-2 members and prevention of apoptosis. Herein, we have demonstrated that VEGF is elevated in the plasma of CLL patients compared to normal individuals. We have previously shown that the growth factor, lysophospatidic acid (LPA), is a survival factor in CLL and its receptor LPA1 is up-regulated in CLL cells (J Biol Chem, 280:9498, 2005). Now, we demonstrate that inhibiting VEGF receptor activation blocks the survival response seen with LPA in CLL. LPA treatment was found to induce VEGF mRNA and protein levels within 1 hour. LPA receptor inhibitor Ki16425 blocked the VEGF production and reversed the protective effect of LPA against apoptosis. Combining LPA and VEGF failed to increase survival responses in these cells. In addition, LPA protection against fludarabine and TRAIL induced apoptosis was eliminated using the VEGF receptor kinase inhibitor, epigallocatechin-3-gallate (EGCG), which is present in green tea, or VEGFR:Fc, that inhibits VEGF receptor activation. Furthermore, LPA induced AKT activation and up-regulation of the expression of the Bcl-2 family member, Mcl-1, were eliminated by the VEGF receptor inhibitor. Thus, the protective effect of LPA against apoptosis in CLL is related to increased production of VEGF. Targeting the LPA pathway similar to the VEGF pathway may thus be a novel approach for the treatment of CLL.

In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3181-3187 ◽  
Author(s):  
Haijuan Chen ◽  
Andy T. Treweeke ◽  
Dave C. West ◽  
Kathleen J. Till ◽  
John C. Cawley ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Culture Media ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Vegf Protein

Abstract Expansion of primary solid tumors and their malignant dissemination are angiogenesis-dependent. Vascular endothelial growth factor (VEGF) is the key factor playing a pivotal role in solid tumor-induced angiogenesis. Recent studies indicate that angiogenesis may also be involved in the pathogenesis of certain hemic malignancies, including B-cell chronic lymphocytic leukemia (B-CLL). Mechanisms underlying angiogenesis in B-CLL and the role of VEGF in this process are incompletely understood. In this study, it was examined whether angiogenically functional VEGF is produced by B-CLL cells. Immunohistochemical staining with antibodies against VEGF and CD34, an endothelial cell marker, demonstrated the presence of VEGF protein and abundant blood vessels in infiltrated lymphoreticular tissues. Low levels of VEGF were detected by ELISA in the culture media of unstimulated cells; this was enhanced up to 7-fold by hypoxic stimulation. SDS-PAGE and Western blot analysis of the concentrated culture media showed 2 isoforms of VEGF protein with molecular weights of 28 and 42 kd, respectively. RNA hybridization showed that these cells expressed VEGF mRNA. Reverse transcription–polymerase chain reaction, combined with nucleotide sequence analysis, revealed that the predominantly expressed isoforms were VEGF121 and VEGF165. Moreover, 3H-thymidine incorporation and an in vivo angiogenic assay demonstrated that the VEGF produced by CLL cells can induce angiogenesis by stimulating endothelial cell proliferation. In conclusion, this study shows that B-CLL cells produce VEGF and demonstrates the angiogenic effects of this growth factor, which may be relevant for the tissue phase of the disease.

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