Abstract
Understanding the intricate cellular components of the bone marrow microenvironment can lead to the discovery of novel extrinsic factors that are responsible for the initiation and progression of leukemic disease. We have shown that endothelial cells (ECs) provide a fertile niche that allows for the propagation of primitive and aggressive leukemic clones. Activation of the ECs by vascular endothelial growth factor (VEGF)-A provides cues that enable leukemic cells to proliferate at higher rates and also increases the adhesion of leukemia to ECs. Vascular endothelial growth factor A-activated ECs decrease the efficacy of chemotherapeutic agents to target leukemic cells. Inhibiting VEGF-dependent activation of ECs by blocking their signaling through VEGF receptor 2 increases the susceptibility of leukemic cells to chemotherapy. Therefore, the development of drugs that target the activation state of the vascular niche could prove to be an effective adjuvant therapy in combination with chemotherapeutic agents.
Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Animals
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Antineoplastic Agents / pharmacology
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Bone Marrow / drug effects
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Bone Marrow / metabolism*
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Bone Marrow / pathology
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Cell Adhesion
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Cell Line, Transformed
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Cell Proliferation
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Cellular Microenvironment
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Clone Cells
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Coculture Techniques
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Disease Models, Animal
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Regulation, Leukemic*
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Human Umbilical Vein Endothelial Cells / pathology
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Humans
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Signal Transduction
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Vascular Endothelial Growth Factor A / pharmacology*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / genetics*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Kdr protein, mouse
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Vascular Endothelial Growth Factor Receptor-2