Hartman Institute for Therapeutic Organ Regeneration

Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy.

TitleVascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy.
Publication TypeJournal Article
Year of Publication2002
AuthorsDias S, Choy M, Alitalo K, Rafii S
JournalBlood
Volume99
Issue6
Pagination2179-84
Date Published2002 Mar 15
ISSN0006-4971
KeywordsCell Division, Cell Survival, Cytokines, Drug Resistance, Neoplasm, Endothelial Growth Factors, Endothelium, Vascular, Humans, Leukemia, Paracrine Communication, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Signal Transduction, Tumor Cells, Cultured, Umbilical Cord, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-3
Abstract

Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4(+) leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.

DOI10.1182/blood.v99.6.2179
Alternate JournalBlood
PubMed ID11877295
Grant ListR01 HL 58707 / HL / NHLBI NIH HHS / United States
R01 HL 61849 / HL / NHLBI NIH HHS / United States
R01 HL 66592 / HL / NHLBI NIH HHS / United States
R01 HL 67839 / HL / NHLBI NIH HHS / United States

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Hartman Institute for Therapeutic Organ Regeneration
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