Blockade of Delta-Like Ligand 4 Signaling Inhibits Both Growth and Angiogenesis of Pancreatic Cancer

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.

[1]  Gavin Thurston,et al.  Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis , 2006, Nature.

[2]  A. Harris,et al.  Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer , 2006, Clinical Cancer Research.

[3]  B. Lewis.  Development of the pancreas and pancreatic cancer. , 2006, Endocrinology and metabolism clinics of North America.

[4]  R. McKay,et al.  Notch controls proliferation and differentiation of stem cells in a dose‐dependent manner , 2006, The European journal of neuroscience.

[5]  Zhiwei Wang,et al.  Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells , 2006, Molecular Cancer Therapeutics.

[6]  D. Stupack,et al.  A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. , 2006, The Journal of clinical investigation.

[7]  A. Harris,et al.  Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. , 2006, Blood.

[8]  Napoleone Ferrara,et al.  VEGF as a Therapeutic Target in Cancer , 2005, Oncology.

[9]  Adrian L Harris,et al.  Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. , 2005, Cancer research.

[10]  R. Benedito,et al.  Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles. , 2005, Gene expression patterns : GEP.

[11]  D. Gough,et al.  Variants of the tissue-sensor array window chamber. , 2005, American journal of physiology. Heart and circulatory physiology.

[12]  T. Giordano,et al.  Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. , 2005, Cancer cell.

[13]  W. Vainchenker,et al.  Notch/Delta4 Interaction in Human Embryonic Liver CD34+ CD38− Cells: Positive Influence on BFU‐E Production and LTC‐IC Potential Maintenance , 2005, Stem cells.

[14]  Gavin Thurston,et al.  Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Tasuku Honjo,et al.  Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. , 2004, Genes & development.

[16]  Janet Rossant,et al.  Dosage-sensitive requirement for mouse Dll4 in artery development. , 2004, Genes & development.

[17]  D. Wolf,et al.  Endothelial progenitor cells: A source for therapeutic vasculogenesis? , 2004, Journal of cellular and molecular medicine.

[18]  T. Asahara,et al.  Endothelial progenitor cells for postnatal vasculogenesis. , 2004, American journal of physiology. Cell physiology.

[19]  Manfred Gessler,et al.  The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. , 2004, Genes & development.

[20]  W. Vainchenker,et al.  Membrane-bound Delta-4 Notch ligand reduces the proliferative activity of primitive human hematopoietic CD34+CD38low cells while maintaining their LTC-IC potential , 2004, Leukemia.

[21]  R. Callahan,et al.  Notch Signaling in Mammary Development and Oncogenesis , 2004, Journal of Mammary Gland Biology and Neoplasia.

[22]  M. Hebrok,et al.  Development and Cancer: Lessons Learned in the Pancreas , 2004, Cell cycle.

[23]  K. Raj,et al.  The role of Notch in tumorigenesis: oncogene or tumour suppressor? , 2003, Nature Reviews Cancer.

[24]  Joe T. Lin,et al.  Tissue window chamber system for validation of implanted oxygen sensors. , 2003, American journal of physiology. Heart and circulatory physiology.

[25]  R. Hruban,et al.  Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. , 2003, Cancer cell.

[26]  J. Folkman,et al.  Treatment of Human Pancreatic Cancer in Mice with Angiogenic Inhibitors , 2003, World Journal of Surgery.

[27]  Larry Kedes,et al.  HES and HERP families: Multiple effectors of the notch signaling pathway , 2003, Journal of cellular physiology.

[28]  J. Folkman,et al.  Angiogenesis Inhibitors: A New Class of Drugs , 2003, Cancer biology & therapy.

[29]  R Bicknell,et al.  Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. , 2001, Differentiation; research in biological diversity.

[30]  J. Sundberg,et al.  Notch signaling is essential for vascular morphogenesis in mice. , 2000, Genes & development.

[31]  W. Richards,et al.  Dll4, a novel Notch ligand expressed in arterial endothelium. , 2000, Genes & development.

[32]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[33]  S. Egawa,et al.  Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. , 2000, Cancer research.

[34]  S. Ben‐Sasson,et al.  Anticancer drug targets: approaching angiogenesis. , 1999, The Journal of clinical investigation.

[35]  S. Artavanis-Tsakonas,et al.  Notch Signaling : Cell Fate Control and Signal Integration in Development , 1999 .

[36]  L. Ding,et al.  Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models. , 1999, Cancer research.

[37]  J. Lewis,et al.  Notch signalling and the control of cell fate choices in vertebrates. , 1998, Seminars in cell & developmental biology.

[38]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[40]  Bing Li,et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo , 1993, Nature.

[41]  A. Lee,et al.  Microvessel quantitation and prognosis in invasive breast carcinoma. , 1992, Human pathology.

[42]  R. Kerbel,et al.  Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti‐cancer therapeutic agents , 1991, BioEssays : news and reviews in molecular, cellular and developmental biology.

[43]  J. Folkman.  What is the evidence that tumors are angiogenesis dependent? , 1990, Journal of the National Cancer Institute.

[44]  M. Koyama,et al.  An improved colorimetric assay for interleukin 2. , 1986, Journal of immunological methods.

[45]  S. Matsuno,et al.  Establishment of a human pancreatic cancer cell line and detection of pancreatic cancer associated antigen. , 1984, The Tohoku journal of experimental medicine.

[46]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[47]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.