title: Cross-talk between leukemic and endothelial cells promotes angiogenesis by VEGF activation of the Notch/Dll4 pathway.
abstract: Angiogenesis is suggested to be important for leukemogenesis and chemosensitivity in acute myeloid leukemia (AML). The vascular endothelial growth factor (VEGF) and Notch/Dll4 pathways have been identified as critical in the regulation of embryonic vascular development and tumor angiogenesis. However, the potential role of the Notch/Dll4 pathway in leukemia-endothelium cross-talk and its functional link with VEGF remains obscure. This study assessed the expression of VEGF and Notch/Dll4 pathway molecules in primary AML and investigated their biological function in the coculture of endothelial cells with AML cells. The results demonstrated that bone marrow vascularity in the newly diagnosed AML patients was increased and correlated with high VEGF and Dll4 expression. Patients with untreated AML expressed higher levels of VEGFR2, Notch1, Dll4 and Hes1 than healthy controls. Moreover, the activation of the Notch/Dll4 pathway is associated with poor prognosis in AML. In addition, AML cells were shown to increase endothelial cell proliferation in Transwell coculture. This was associated with concomitant activation of the Notch/Dll4 pathway and upregulation of its downstream genes, such as matrix metalloproteinases, resulting in the enhancement of endothelial cell migration and tube formation. Our study also showed that upregulation of Dll4 expression in AML cells by cDNA transfection suppressed VEGF-induced endothelial cell proliferation and angiogenesis in direct contact coculture. These results elucidate a novel mechanism by which the interplay between AML and endothelial cells promotes angiogenesis through the Notch/Dll4 pathway. Modulation of this pathway may, therefore, hold promise as a novel antiangiogenic strategy for the treatment of AML.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Zhang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.forename: Daoxin
authors.initials: D
authors.lastname: Ma
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Shuang
authors.initials: S
authors.lastname: Yu
authors.forename: Xiulian
authors.initials: X
authors.lastname: Sun
authors.forename: William
authors.initials: W
authors.lastname: Tse
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000098:blood supply / Q000473:pathology; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2