Epithelial and stromal cell urokinase plasminogen activator receptor expression differentially correlates with survival in rectal cancer stages B and C patients

PLoS One. 2015 Feb 18;10(2):e0117786. doi: 10.1371/journal.pone.0117786. eCollection 2015.

Abstract

Urokinase plasminogen activator receptor (uPAR) has been proposed as a potential prognostic factor for colorectal cancer (CRC) patient survival. However, CRC uPAR expression remains controversial, especially regarding cell types where uPAR is overexpressed (e.g., epithelium (uPARE) or stroma-associated cells (uPARS)) and associated prognostic relevance. In this study, two epitope-specific anti-uPAR monoclonal antibodies (MAbs) could discriminate expression of uPARE from uPARS and were used to examine this association with survival of stages B and C rectal cancer (RC) patients. Using immunohistochemistry, MAbs #3937 and R4 were used to discriminate uPARE from uPARS respectively in the central and invasive frontal regions of 170 stage B and 179 stage C RC specimens. Kaplan-Meier and Cox regression analyses were used to determine association with survival. uPAR expression occurred in both epithelial and stromal compartments with differential expression observed in many cases, indicating uPARE and uPARS have different cellular roles. In the central and invasive frontal regions, uPARE was adversely associated with overall stage B survival (HR = 1.9; p = 0.014 and HR = 1.5; p = 0.031, respectively) reproducing results from previous studies. uPARS at the invasive front was associated with longer stage C survival (HR = 0.6; p = 0.007), reflecting studies demonstrating that macrophage peritumoural accumulation is associated with longer survival. This study demonstrates that different uPAR epitopes should be considered as being expressed on different cell types during tumour progression and at different stages in RC. Understanding how uPARE and uPARS expression affects survival is anticipated to be a useful clinical prognostic marker of stages B and C RC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / metabolism
  • Epithelial Cells / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Receptors, Urokinase Plasminogen Activator / metabolism*
  • Rectal Neoplasms / metabolism*
  • Rectal Neoplasms / pathology*
  • Rectal Neoplasms / therapy
  • Stromal Cells / metabolism
  • Survival Analysis
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Receptors, Urokinase Plasminogen Activator

Grants and funding

This study was supported with research project grant funding from the NHMRC (#1010303), Cancer Council NSW (RG10-04 & RG08-16), and a Macquarie University MQSN grant; and supported through the Australian School of Advanced Medicine (ASAM), Macquarie University, Concord Repatriation General Hospital Diagnostic Pathology, MQ Biofocus, and Biomolecular Frontiers Research Centres. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.