title: Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer.
abstract: Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Han Hee
authors.initials: HH
authors.lastname: Dong
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: De-yu
authors.initials: DY
authors.lastname: Shen
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Edna
authors.initials: E
authors.lastname: Mora
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ju-Won
authors.initials: JW
authors.lastname: Roh
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.forename: Masato
authors.initials: M
authors.lastname: Nishimura
authors.forename: Blake W
authors.initials: BW
authors.lastname: Goodman
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jaffe
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Michael T
authors.initials: MT
authors.lastname: Deavers
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein; D040301:Vascular Endothelial Growth Factor Receptor-2