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Vascular endothelial growth factor-related pathways in hemato-lymphoid malignancies.

Medinger M, Fischer N, Tzankov A - J Oncol (2010)

Bottom Line: Angiogenesis is essential for malignant tumor growth.The most important proangiogenic agent is vascular endothelial growth factor (VEGF), activating VEGF receptors 1 and 2.The available data on angiogenesis in hemato-lymphoid malignancies, such as acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and lymphomas, point towards the significance of autocrine and paracrine VEGF-mediated effects for proliferation and survival of leukemia/lymphoma cells in addition to tumor vascularization.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.

ABSTRACT
Angiogenesis is essential for malignant tumor growth. This has been documented for solid tumors, and there is an emerging evidence suggesting that tumor progression of hematolymphoid malignancies also depends on the induction of new blood vessel formation. The most important proangiogenic agent is vascular endothelial growth factor (VEGF), activating VEGF receptors 1 and 2. The available data on angiogenesis in hemato-lymphoid malignancies, such as acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and lymphomas, point towards the significance of autocrine and paracrine VEGF-mediated effects for proliferation and survival of leukemia/lymphoma cells in addition to tumor vascularization. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. Several antiangiogenic agents targeting VEGF-related pathways are also being utilized in clinical trials for the treatment of hemato-lymphoid malignancies, and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hemato-lymphoid malignancies and the translation of such basic findings into clinical studies.

No MeSH data available.


Related in: MedlinePlus

Possible vascular endothelial growth factor- (VEGF) and VEGF receptor-related (e.g., Flk-1, i.e., VEGFR-2) autocrine and paracrine loops in hemato-lymphoid neoplasms; insert: receptor tyrosine kinase activity and signaling cascades through VEGFR-2.
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Related In: Results  -  Collection


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fig1: Possible vascular endothelial growth factor- (VEGF) and VEGF receptor-related (e.g., Flk-1, i.e., VEGFR-2) autocrine and paracrine loops in hemato-lymphoid neoplasms; insert: receptor tyrosine kinase activity and signaling cascades through VEGFR-2.

Mentions: The key mediator of angiogenesis is the vascular endothelial growth factor (VEGF). Its expression is regulated by a plethora of intrinsic and extrinsic factors, with hypoxia and hypoglycemia being the major stimuli [6]. Hypoxia-induced transcription of VEGF mRNA is mediated by binding of hypoxia-inducible factor 1 (HIF-1) [7]. Cytokines may also modulate angiogenesis by regulating VEGF expression, for example, tumor necrosis factor (TNF)-α increases VEGF mRNA in glioma cells [8], and transforming growth factor (TGF)-β results in the induction of VEGF mRNA and protein in human lung adenocarcinoma cells [9]. In solid tumors, intratumoral hypoxia and HIF-1 mediation have been found to be a key angiogenesis triggering event [10]. Less is known about the exact trigger mechanisms of VEGF expression in hemato-lymphoid tumors, but mechanisms analogous to those observed in solid tumors are anticipated [11, 12]. Tight control of angiogenesis is maintained by a balance of endogenous antiangiogenic and proangiogenic factors. VEGF has a key, rate-limiting role in promoting tumor angiogenesis and exerts its effects by binding to one of three tyrosine kinase receptors (Figure 1): VEGF receptor-1 (VEGFR-1; fms-like tyrosine kinase-1, Flt-1), VEGFR-2 (human kinase domain region, KDR/murine fetal liver kinase-1, Flk-1), and VEGFR-3 (Flt-4). VEGFR-1 (ligands include VEGF-A, -B, and placental growth factor [PIGF]) and VEGFR-2 (ligands include VEGF-A, -C, and -D) are predominantly expressed on vascular endothelial cells, and activation of VEGFR-2 appears to be both necessary and sufficient to mediate VEGF-dependent angiogenesis and induction of vascular permeability [13, 14]. Both receptor tyrosine kinases are expressed in all adult endothelial cells except the brain. VEGFR-1 is also expressed on hematopoietic stem cells (HSC), vascular smooth muscle cells, monocytes, and leukemic cells [15, 16], while VEGFR-2 is expressed on endothelial progenitor cells and megakaryocytes [17, 18]. Although the exact contribution of VEGFR-1 signaling to angiogenesis is unclear, it has been shown that VEGFR-1 directly cooperates with VEGFR-2 via heterodimerization, as well as binding two additional VEGF homologues, VEGF-B and PIGF [19]. VEGFR-3, largely restricted to lymphatic endothelial cells, binds the VEGF homologues VEGF-C and VEGF-D and may play an important role in the regulation of lymphangiogenesis.


Vascular endothelial growth factor-related pathways in hemato-lymphoid malignancies.

Medinger M, Fischer N, Tzankov A - J Oncol (2010)

Possible vascular endothelial growth factor- (VEGF) and VEGF receptor-related (e.g., Flk-1, i.e., VEGFR-2) autocrine and paracrine loops in hemato-lymphoid neoplasms; insert: receptor tyrosine kinase activity and signaling cascades through VEGFR-2.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2875768&req=5

fig1: Possible vascular endothelial growth factor- (VEGF) and VEGF receptor-related (e.g., Flk-1, i.e., VEGFR-2) autocrine and paracrine loops in hemato-lymphoid neoplasms; insert: receptor tyrosine kinase activity and signaling cascades through VEGFR-2.
Mentions: The key mediator of angiogenesis is the vascular endothelial growth factor (VEGF). Its expression is regulated by a plethora of intrinsic and extrinsic factors, with hypoxia and hypoglycemia being the major stimuli [6]. Hypoxia-induced transcription of VEGF mRNA is mediated by binding of hypoxia-inducible factor 1 (HIF-1) [7]. Cytokines may also modulate angiogenesis by regulating VEGF expression, for example, tumor necrosis factor (TNF)-α increases VEGF mRNA in glioma cells [8], and transforming growth factor (TGF)-β results in the induction of VEGF mRNA and protein in human lung adenocarcinoma cells [9]. In solid tumors, intratumoral hypoxia and HIF-1 mediation have been found to be a key angiogenesis triggering event [10]. Less is known about the exact trigger mechanisms of VEGF expression in hemato-lymphoid tumors, but mechanisms analogous to those observed in solid tumors are anticipated [11, 12]. Tight control of angiogenesis is maintained by a balance of endogenous antiangiogenic and proangiogenic factors. VEGF has a key, rate-limiting role in promoting tumor angiogenesis and exerts its effects by binding to one of three tyrosine kinase receptors (Figure 1): VEGF receptor-1 (VEGFR-1; fms-like tyrosine kinase-1, Flt-1), VEGFR-2 (human kinase domain region, KDR/murine fetal liver kinase-1, Flk-1), and VEGFR-3 (Flt-4). VEGFR-1 (ligands include VEGF-A, -B, and placental growth factor [PIGF]) and VEGFR-2 (ligands include VEGF-A, -C, and -D) are predominantly expressed on vascular endothelial cells, and activation of VEGFR-2 appears to be both necessary and sufficient to mediate VEGF-dependent angiogenesis and induction of vascular permeability [13, 14]. Both receptor tyrosine kinases are expressed in all adult endothelial cells except the brain. VEGFR-1 is also expressed on hematopoietic stem cells (HSC), vascular smooth muscle cells, monocytes, and leukemic cells [15, 16], while VEGFR-2 is expressed on endothelial progenitor cells and megakaryocytes [17, 18]. Although the exact contribution of VEGFR-1 signaling to angiogenesis is unclear, it has been shown that VEGFR-1 directly cooperates with VEGFR-2 via heterodimerization, as well as binding two additional VEGF homologues, VEGF-B and PIGF [19]. VEGFR-3, largely restricted to lymphatic endothelial cells, binds the VEGF homologues VEGF-C and VEGF-D and may play an important role in the regulation of lymphangiogenesis.

Bottom Line: Angiogenesis is essential for malignant tumor growth.The most important proangiogenic agent is vascular endothelial growth factor (VEGF), activating VEGF receptors 1 and 2.The available data on angiogenesis in hemato-lymphoid malignancies, such as acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and lymphomas, point towards the significance of autocrine and paracrine VEGF-mediated effects for proliferation and survival of leukemia/lymphoma cells in addition to tumor vascularization.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.

ABSTRACT
Angiogenesis is essential for malignant tumor growth. This has been documented for solid tumors, and there is an emerging evidence suggesting that tumor progression of hematolymphoid malignancies also depends on the induction of new blood vessel formation. The most important proangiogenic agent is vascular endothelial growth factor (VEGF), activating VEGF receptors 1 and 2. The available data on angiogenesis in hemato-lymphoid malignancies, such as acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and lymphomas, point towards the significance of autocrine and paracrine VEGF-mediated effects for proliferation and survival of leukemia/lymphoma cells in addition to tumor vascularization. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. Several antiangiogenic agents targeting VEGF-related pathways are also being utilized in clinical trials for the treatment of hemato-lymphoid malignancies, and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hemato-lymphoid malignancies and the translation of such basic findings into clinical studies.

No MeSH data available.


Related in: MedlinePlus