Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery

PLoS One. 2013;8(2):e56760. doi: 10.1371/journal.pone.0056760. Epub 2013 Feb 27.

Abstract

Introduction: Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity.

Aims and methods: Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated.

Results: The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance.

Conclusion: This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / surgery
  • Cell Membrane / metabolism
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lymph Nodes / metabolism*
  • Lymph Nodes / pathology*
  • Lymphatic Metastasis / pathology*
  • Male
  • Middle Aged
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / surgery*
  • Prognosis
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / deficiency*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Staining and Labeling

Substances

  • Receptors, TNF-Related Apoptosis-Inducing Ligand

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) with grants DFG TO 605/2-1 to EDT and DFG GA762/3-2 to EG and by the Else Kröner-Fresenius Stiftung with the grant 2011_A226 to EDT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.