Blockade of delta-like ligand 4 signaling inhibits both growth and angiogenesis of pancreatic cancer.
OBJECTIVE
The Notch signaling pathway is evolutionarily conserved and regulates cell-fate decisions in a variety of organ development. Previous studies have shown that delta-like ligand 4 (DLL4), one of transmembranous Notch ligands, is up-regulated at the site of tumor growth, especially of tumor angiogenesis. In this study, we examined the effects of the DLL4-Notch signaling on tumor angiogenesis using the neutralizing monoclonal antibodies against DLL4.


METHODS
The neutralizing monoclonal antibodies against murine DLL4 (HMD4-2) were newly established, and their effects on tumor growth and angiogenesis were evaluated using the mice subcutaneously implanted human pancreatic cancer cells (PK-1) in the dorsal flank area. To further assess the effects on tumor angiogenesis, PK-1 cells were implanted in skinfold chambers inserted on the dorsal area of the mice.


RESULTS
Treatment (intraperitoneally) with HMD4-2 suppressed the in vivo tumor growth with marked decrease of tumor vasculature and had no direct inhibitory effect on PK-1 cells in vitro. Real-time sequential analysis using the skinfold chamber model revealed the antiangiogenic effect of HMD4-2.


CONCLUSIONS
These results suggests that cell-to-cell interaction via DLL4-Notch signaling pathway has been implicated in tumor angiogenesis, and control of this pathway can be a new therapeutic approach to solid tumor.
Oishi
Hidekazu
H
Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Sunamura
Makoto
M
Egawa
Shinichi
S
Motoi
Fuyuhiko
F
Unno
Michiaki
M
Furukawa
Toru
T
Habib
Nagy A
NA
Yagita
Hideo
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D009500:Neutralization Tests; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein