Title | Activation of the vascular niche supports leukemic progression and resistance to chemotherapy. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Poulos MG, Gars EJ, Gutkin MC, Kloss CC, Ginsberg M, Scandura JM, Rafii S, Butler JM |
Journal | Exp Hematol |
Volume | 42 |
Issue | 11 |
Pagination | 976-986.e3 |
Date Published | 2014 Nov |
ISSN | 1873-2399 |
Keywords | Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Bone Marrow, Cell Adhesion, Cell Line, Transformed, Cell Proliferation, Cellular Microenvironment, Clone Cells, Coculture Techniques, Disease Models, Animal, Drug Resistance, Neoplasm, Gene Expression Regulation, Leukemic, Human Umbilical Vein Endothelial Cells, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplastic Stem Cells, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2 |
Abstract | <p>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.</p> |
DOI | 10.1016/j.exphem.2014.08.003 |
Alternate Journal | Exp Hematol |
PubMed ID | 25179751 |
PubMed Central ID | PMC4254082 |
Grant List | R01 HL097797 / HL / NHLBI NIH HHS / United States |