title: Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy.
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.
authors.affiliation: Division of Hematology/Oncology, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10021, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Dias
authors.forename: Margaret
authors.initials: M
authors.lastname: Choy
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014470:Umbilical Cord; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
chemical_list: D016207:Cytokines; D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3