Delta like ligand 4 induces impaired chemo-drug delivery and enhanced chemoresistance in pancreatic cancer

Cancer Lett. 2013 Mar 1;330(1):11-21. doi: 10.1016/j.canlet.2012.11.015. Epub 2012 Nov 27.

Abstract

The stubborn chemoresistance of pancreatic ductal adenocarcinoma (PDA) is simultaneously influenced by tumor parenchymal and stromal factors, and the ctritical role of Notch ligand Delta-like 4 (DLL4) in the regulation of tumor malignancies has been observed. DLL4 positive expression ratio between duct cells from clinical tumor and adjacent tissues was statistically significant, and the overactivation of DLL4/Notch pathway enhanced the phenotype of EMT and cancer stem cell, even can induce multi-chemoresistance in vitro. Notably, the accompanied defective angiogenesis directly induced inefficient chemo-drug delivery in vivo. Collectively, overexpressed DLL4 on neoplastic cells can enhance chemoresistance through angiogenesis-dependent/independent mechanisms in PDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Doxorubicin / pharmacology
  • Drug Delivery Systems
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Receptor, Notch1 / biosynthesis
  • Receptor, Notch2 / biosynthesis
  • Xenograft Model Antitumor Assays

Substances

  • Antibiotics, Antineoplastic
  • DLL4 protein, human
  • Intercellular Signaling Peptides and Proteins
  • NOTCH1 protein, human
  • NOTCH2 protein, human
  • Receptor, Notch1
  • Receptor, Notch2
  • Doxorubicin