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 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

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.

scholarly journals Does Adiponectin Act as an Antiangiogenic Factor in B-Cell Chronic Lymphocytic Leukemia?

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Stefano Molica ◽  
Giovanna Digiesi ◽  
Angelo Vacca ◽  
Rosanna Mirabelli ◽  
Katia Todoerti ◽  
...  
Keyword(s):  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Gene Transcript ◽  
Vascular Endothelial ◽  
Binet Stage ◽  
Endothelial Growth Factor ◽  
Cell Chronic Lymphocytic Leukemia

Angiogenesis is involved in the pathogenesis of B-cell chronic lymphocytic leukemia (CLL), and high microvascular density has been found in CLL to be associated with a poor prognosis. In this study, we assessed serum levels of adiponectin in 69 patients with Binet stage A B-CLL, and these values were retrospectively correlated with bone marrow (BM) microvessel area and serum levels of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), angiogenin, PECAM-1 (CD31), matrix metalloproteinase-9 (MMP-9), interleukin-8 (IL-8), syndecan-1, and the percentage ofCD38+orZAP-70+CLL cells. The positive correlation between serum levels of adiponectin and VEGF (P=.03) does not translate into an increase of the extent of BM angiogenesis (P=.404), FGF-2 (P=.348), angiogenin (P=.402), and CD31 (P=.248) serum concentrations. Accordingly, IL-8 (P=.175), syndecan-1 (P=.06), and MMP-9 (P=.144) circulating levels were not likely to reflect adiponectin concentration. Furthermore, patients with higher levels of adiponectin had a more favorable biological profile as defined by a lower number of bothCD38−(r=−0.294;P=.02) andZAP-70+(r=−0.285;P=.04). Finally, we evaluated the presence of adiponectin in B-CLL cells at gene expression level. RMA intensity values for adiponectin gene transcript denote a homogeneous low expression in B-CLL cells, whereas VEGF transcript was highly expressed with a degree of interpatient variability. Overall, these data seem to indicate that adiponectin could be involved as an antiangiogenic factor in B-CLL.

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 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.

Sign in / Sign up

Export Citation Format

Share Document