High MUC2 expression in ovarian cancer is inversely associated with the M1/M2 ratio of tumor-associated macrophages and patient survival time

PLoS One. 2013 Dec 6;8(12):e79769. doi: 10.1371/journal.pone.0079769. eCollection 2013.

Abstract

Mucin 2 (MUC2) is a mucin molecule aberrantly expressed by ovarian cancer cells. Previous in vitro studies have indicated that MUC2 promotes cancer growth and metastasis through a tumor-associated macrophage (TAM)-dependent mechanism. However, this mechanism has never been linked to clinical oncology, and its prognostic significance needed to be clarified. Here, we collected 102 consecutive ovarian cancer specimens and used the multiple immuno-histo-chemical/-fluorescent technique to determine the correlations between the MUC2 expression status, the ratio of M1/M2 TAMs and the densities of cyclooxygenase-2 (COX-2)(+) TAMs and COX-2(+) cancer cells. The Kaplan-Meier survival analysis and multivariate Cox regression analysis were used to evaluate the prognostic influences of these parameters. As a result, we found that the MUC2 overexpression (immunostaining ++/+++) was significantly correlated with a reduced ratio of M1/M2 TAMs (p<0.001), an increased density of COX-2(+) TAMs (p<0.001) and an increased density of COX-2(+) cancer cells (p=0.017). Moreover, most of the M2 TAMs (93%-100%) and COX-2(+) TAMs (63%-89%) overlapped; and the COX-2(+) cancer cells were frequently observed near the COX-2(+) TAMs. In the Cox regression analysis, MUC2 overexpression was found to be an independent prognostic factor for ovarian cancer patients, of which the hazard ratio (HR) was 2.354 (95% confidence interval (CI): 1.031-10.707, p=0.005). Also, the reduced ratio of M1/M2 TAMs and the increased densities of COX-2(+) TAMs and COX-2(+) cancer cells were demonstrated to be the predictors of poor prognosis, among which the reduced M1/M2 ratio possessed the highest HR (1.767, 95% CI: 1.061-6.957, p=0.019). All these findings revealed that MUC2 can concurrently exert M2-polarizing and COX-2-inducing effects on TAMs, by which it causes an imbalanced TAM M1-/M2-polarization pattern and induces local PGE2 synthesis (in both TAMs and cancer cells). The positive feedback between local PGE2 synthesis and TAM M2-polarization accelerates ovarian cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Mucinous / genetics*
  • Adenocarcinoma, Mucinous / metabolism
  • Adenocarcinoma, Mucinous / mortality
  • Adenocarcinoma, Mucinous / pathology
  • Aged
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / metabolism
  • Cystadenocarcinoma, Serous / mortality
  • Cystadenocarcinoma, Serous / pathology
  • Dinoprostone / metabolism
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Macrophages / classification
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Middle Aged
  • Mucin-2 / genetics*
  • Mucin-2 / metabolism
  • Neoplasm Staging
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • Prognosis
  • Proportional Hazards Models
  • Signal Transduction
  • Survival Analysis

Substances

  • MUC2 protein, human
  • Mucin-2
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone

Grants and funding

This work was supported by grants from the Key Disciplines and Specialties Foundation of the Shanghai Health Bureau, the Key Disciplines Foundation of the Shanghai Education Commission (grant number 08YZ43), the Science Research Foundation of the Shanghai Science and Technology Commission (grant number 12411950200), the Key Discipline Project of Renji Hospital, School of Medicine, Shanghai Jiaotong University, the China Post-doctoral Science Foundation (grant number 2011M500795), and the National Natural Science Foundation of China (grant numbers 81272882 and 81072137). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.