Vascular Endothelial Growth factor, a possible paracrine growth factor in human acute myeloid leukemia
Department of Hematology/Oncology, University Hospital Eppendorf, Hamburg, Germany. Blood
(Impact Factor: 10.45).
Vascular endothelial growth factor (VEGF) is a multifunctional cytokine involved in angiogenesis, inflammation, and wound healing. It is secreted by a variety of tumor cell lines, including hematopoietic lines. Therefore, we investigated expression of VEGF and its receptors on fresh leukemic blasts. VEGF-specific transcripts were detected by polymerase chain reaction (PCR) in 20 of 28 patients with de novo acute myeloid leukemia (AML) and in 3 of 5 patients with secondary AML. Using immunocytochemistry, we found VEGF protein in 2 leukemic cell lines and in 8 AML patients, in concordance with PCR results. Supernatants of fresh leukemic cells from 24 AML patients contained significantly more VEGF than supernatants from bone marrow cells of 9 normal donors or of CD34-enriched cells from 3 normal volunteer donors as determined by an enzyme-linked immunosorbent assay. VEGF possesses two high-affinity receptors, KDR and FLT1. Using a sensitive nested PCR assay, we detected expression of FLT1 in 10 of 20 patients with de novo AML and 3 of 5 patients with secondary AML. KDR was expressed in 4 of 22 patients with de novo AML and 1 of 4 with secondary AML. To study possible paracrine growth stimulation of AML blasts, endothelial cells from human umbilical cords were incubated with increasing concentrations of VEGF. A dose-dependent increase of granulocyte-macrophage colony-stimulating factor secretion from endothelial cells was identified.
Available from: PubMed Central
- "To the best of our knowledge there have been no studies prior to ours analyzing the correlation between proliferation index and angiogenesis in acute leukemia. VEGF and other angiogenic peptides are involved in autocrine and paracrine stimulation of leukemic cells [7, 9]. Hence we feel a direct relationship between MVD and blast percentage or cellularity might not be possible to establish, as the relation is complex and not linear. "
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ABSTRACT: Angiogenesis and proliferation as measured by microvessel density (MVD) and proliferation index (PI) are essential correlates of malignancy. The aim of our study was to evaluate difference between these values in AML and ALL and also to study the modulation in these parameters following achievement of remission in acute lymphoblastic leukemia. Differences between adult and adolescent cases of acute leukemia in relation to these values were also studied. We also tried to assess the relationship between angiogenesis and proliferation. Fifty-five patients with acute leukemia were included in the study. Trephine biopsies were immunostained with CD34 and factor VIIIrAg to demonstrate angiogenesis measured as MVD. Immunostaining with PCNA and Ki-67 was done to study proliferation. We found a significant increase in MVD and PI in cases when compared with controls (P < 0.0001). In addition cases with ALL had a significantly higher MVD compared to those with AML (P < 0.01). The patients with ALL who went into remission showed a significant reduction in MVD; PI remained high. The cases which did not achieve remission showed no significant reduction in either MVD or PI. All adolescent cases of ALL were similar to adults with respect to MVD and PI.
03/2014; 2014(3):634874. DOI:10.1155/2014/634874
Available from: Zohreh Sanaat
- "The fact that angiogenesis may have an important role in AML and the key regulatory role of the VEGF/VEGFR complex in angiogenesis leads to the performing of studies regarding the role of VEGF in AML [26,27,28]. Fielder et al. reported that the leukemic cells of most patients with AML expressed VEGF-C . Furthermore, Dias et al. demonstrated that VEGF-C, which was released from the endothelium, induced proliferation, promoted survival of AML cells, and protected VEGFR-3–expressing leukemic cells from chemotherapy-induced apoptosis . "
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ABSTRACT: Objective: The crucial role of angiogenesis in the pathophysiology of acute myeloid leukemia (AML) has been proposed. One of the key regulators of angiogenesis is the vascular endothelial growth factor (VEGF). Among the VEGF family, it has been observed that VEGF-A and VEGF-C are expressed by AML cells and mediate leukemic cell proliferation, survival, and resistance to chemotherapy. Emerging evidence, however, suggests that elevated levels of VEGF or a proangiogenic phenotype may impede, rather than promote, early tumor development and progression. As the significance of VEGF-A and VEGF-C levels in the pathogenesis of AML has not been clarified well, the aim of this study is to evaluate gene expression of these angiogenesis promoters and its possible prognostic value in peripheral blood mononuclear cells of Iranian patients with AML.
Materials and Methods: We investigated the mRNA expression of VEGF-A and VEGF-C in peripheral blood mononuclear cells of 27 patients with newly diagnosed AML and 28 healthy controls by quantitative real-time PCR.
Results: Expression of VEGF-C mRNA was significantly lower in AML patients than in healthy controls (p<0.001). However, there was no significant decrement in expression of VEGF-A mRNA of AML patients compared to the control group (p=0.861). VEGF-A and VEGF-C expression were not able to predict clinical outcome.
Conclusion: Our data showed that AML is associated with a decreased expression of VEGF-C mRNA. However, expression levels did not influence the clinical outcome in our study. It seems that angiogenesis is affected by different cytokines other than VEGF-C or VEGF-A, and VEGF is also affected by different cytokines. Taken together, these findings help to provide new insights into the investigation of other angiogenic factors and cytokines that may play roles in the pathogenesis of AML.
Conflict of interest:None declared.
Turkish Journal of Haematology 06/2013; 30(2):137-43. DOI:10.4274/Tjh.2011.0023 · 0.36 Impact Factor
Available from: plosone.org
- "Interestingly, leukemia cells possess the ability to alter BM microenvironments as well as EC behavior. For example, in vitro co-culture of ECs with human AML altered EC behavior in a non-cell-autonomous manner resulting in increased EC proliferation , , . Others have shown that transplanted leukemia cells can disrupt BM niche activity in vivo resulting in abnormal microenvironments . "
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ABSTRACT: In acute myeloid leukemia (AML), the chances of achieving disease-free survival are low. Studies have demonstrated a supportive role of endothelial cells (ECs) in normal hematopoiesis. Here we show that similar intercellular relationships exist in leukemia. We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. In this inflammatory state, activated ECs induce the adhesion of a sub-set of leukemia cells through the cell adhesion molecule E-selectin. These adherent leukemia cells are sequestered in a quiescent state and are unaffected by chemotherapy. The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. Interestingly, differing leukemia subtypes modulate this process to varying degrees, which may explain the varied response of AML patients to chemotherapy and relapse rates. Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. Together, the data defines a new mechanism describing how ECs and leukemia cells interact during leukemogenesis, which could be used to develop novel treatments for those with AML.
PLoS ONE 04/2013; 8(4):e60823. DOI:10.1371/journal.pone.0060823 · 3.23 Impact Factor
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