title: In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo.
abstract: Recent findings implied that the progression of hematologic malignancies, like that of solid tumors, is dependent on neovascularization. Recent studies on patients with acute myeloid leukemia (AML) showed increased levels of leukocyte-associated vascular endothelial growth factor (VEGF) and neovascularization of the bone marrow. Murine (32D, M1) and human (HEL, U937, and UKE-1) leukemic cell lines and freshly isolated leukemic cells were analyzed for the expression of VEGF and VEGF receptor mRNA. The expression of VEGF and VEGF receptors KDR and neuropilin-1 (NRP-1) was detected in these cells. In a murine chloroma model, delivery of VEGF(165) using microencapsulation technology resulted in enhanced tumor growth and vascularization, whereas treatment with a VEGF antagonist soluble NRP-1 (sNRP-1) inhibited tumor angiogenesis and growth. In a systemic leukemia model, survival of mice injected with adenovirus (Ad) encoding for Fc-sNRP-1 (sNRP-1 dimer) was significantly prolonged as compared with mice injected with Ad-LacZ. Further analyses showed a reduction in circulating leukemic cells and infiltration of liver and spleen as well as bone marrow neovascularization and cellularity. Taken together, these results demonstrate that angiogenic factors such as VEGF promote AML progression in vivo. The use of VEGF antagonists as an antiangiogenesis approach offers a potential treatment for AML. Finally, our novel in vivo drug delivery model may be useful for testing the activities of other peptide antiangiogenic factors.
authors.affiliation: Department of Urology, Laboratory for Cellular Therapeutics, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Gunter
authors.initials: G
authors.lastname: Schuch
authors.forename: Marcelle
authors.initials: M
authors.lastname: Machluf
authors.forename: Georg
authors.initials: G
authors.lastname: Bartsch
authors.forename: Masashi
authors.initials: M
authors.lastname: Nomi
authors.forename: Henri
authors.initials: H
authors.lastname: Richard
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.forename: Shay
authors.initials: S
authors.lastname: Soker
mesh_terms: D000208:Acute Disease; D000818:Animals; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D015316:Genetic Therapy; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D039942:Neuropilin-1 / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D013552:Swine; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D020298:U937 Cells / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2