Blockade of delta-like ligand 4 signaling inhibits both growth and angiogenesis of pancreatic cancer

Hidekazu Oishi, Makoto Sunamura, Shinichi Egawa, Fuyuhiko Motoi, Michiaki Unno, Toru Furukawa, Nagy A. Habib, Hideo Yagita

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Objectives: 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.

Original languageEnglish
Pages (from-to)897-903
Number of pages7
JournalPancreas
Volume39
Issue number6
DOIs
Publication statusPublished - 2010 Aug

Keywords

  • DLL4
  • Notch
  • antiangiogenic effect
  • neutralizing mAbs
  • pancreatic cancer
  • tumor angiogenesis

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

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