High expression of delta-like ligand 4 predicts poor prognosis after curative resection for pancreatic cancer

Ann Surg Oncol. 2012 Jul;19 Suppl 3:S464-74. doi: 10.1245/s10434-011-1968-9. Epub 2011 Aug 6.

Abstract

Background: Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor angiogenesis, but its prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. Our aim was to determine whether high DLL4 expression is correlated with poor prognosis after curative resection for PDAC.

Methods: Surgical specimens obtained from 89 patients with PDAC were immunohistochemically assessed for DLL4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression. Prognostic significance of DLL4 expression was evaluated by Kaplan-Meier method and Cox regression. The correlations of DLL4 expression with VEGFR-2 expression, tumor stage, and lymph node metastasis were examined by chi-square test and multivariate logistic regression.

Results: There were 38 (42.7%) and 51 patients who showed high and low DLL4 expression, respectively. Survival curves showed that patients with low DLL4 expression had a significantly better survival than those with high DLL4 expression (P < .001). Multivariate survival analysis demonstrated that high DLL4 expression was independently associated with both reduced overall survival (hazard ratio [HR] 2.24; 95% confidence interval [95% CI] 1.14-4.38) and reduced progression-free survival (HR 2.37; 95% CI 1.22-4.60). Multivariate logistic regression analyses showed that high DLL4 expression was independently associated with both advanced tumor stage (odds ratio [OR] 6.84; 95% CI 2.42-9.36) and lymph node metastasis (OR 3.27; 95% CI 1.04-10.34). We also found a positive correlation between DLL4 and VEGFR-2 expression (P < .001).

Conclusions: High DLL4 expression is significantly associated with poor prognosis for surgically resected PDAC, advanced tumor stage, and lymph node metastasis. Application of adjuvant therapy targeting DLL4-Notch signaling may improve prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Area Under Curve
  • Carcinoma, Pancreatic Ductal / blood
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / secondary
  • Carcinoma, Pancreatic Ductal / surgery
  • Chi-Square Distribution
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kaplan-Meier Estimate
  • Lymphatic Metastasis
  • Lymphocyte Count
  • Male
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Neutrophils
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / surgery
  • Platelet Count
  • Proportional Hazards Models
  • ROC Curve
  • Tumor Burden
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • delta protein
  • Vascular Endothelial Growth Factor Receptor-2