Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus

Am J Gastroenterol. 2004 Sep;99(9):1667-74. doi: 10.1111/j.1572-0241.2004.30733.x.


Objectives: Macrophage chemoattractant protein-1 (MCP-1) is a chemokine-inducing infiltration of macrophages, which can play several roles in tumor growth and metastasis. We have attempted to clarify the relationship between MCP-1 expression and macrophage infiltration in esophageal squamous cell carcinoma (SCC).

Methods: Paraffin-embedded sections of tissue samples taken from 56 patients with esophageal SCC after curative surgery were immunohistochemically stained for MCP-1, CC chemokine receptor 2 (CCR-2), and thymidine phosphorylase (TP). Macrophage recruitment in SCC was evaluated by monocytic count based on CD68 immunostaining. Microvessels immunostained for Factor VIII-related antigen were counted in SCC, and microvessel density (MVD) was determined. Ki-67 labeling index was calculated based on Ki-67 immunostaining, and an apoptotic index was calculated based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling.

Results: MCP-1 was expressed in cancer cells of 31 SCC (55.4%) and in stromal cells mainly identified as macrophages of 16 SCC (28.6%). CCR-2 was expressed in stromal cells of all SCC and in vascular endothelial cells of 15 SCC (26.8%). There was a significant correlation between the expression of MCP-1 in cancer cells and of CCR-2 in stromal cells. TP was expressed in stromal cells in 76.7% of the SCC. Monocytic count, MVD, and Ki-67 LI in SCC with MCP-1 expression in cancer cells were higher than that without, and apoptotic index in SCC with MCP-1 expression in cancer cells were lower than that without. Furthermore, the monocytic count was positively correlated with MVD, while it was inversely correlated with apoptotic index. Clinicopathologically, MCP-1 expression in cancer cells was correlated with venous invasion, distant metastasis, and lymph node metastasis. Monocytic count in SCC with venous invasion, distant metastasis, or lymph node metastasis was higher than that without them. Five-year survival rate in the patients with high monocytic count or MCP-1 expression was worse than that with a low monocytic count or without MCP-1 expression.

Conclusions: These results suggest that MCP-1 expression and macrophage infiltration is associated with angiogenic promotion in esophageal SCC. MCP-1 expression may be interactively associated with macrophage infiltration in esophageal SCC; MCP-1 may play an important role in tumor angiogenesis through production of angiogenic factors, such as TP, by recruited macrophages in esophageal SCC. Furthermore, CCR-2 expression in vascular endothelial cells may participate partially in angiogenesis. Clinicopathologically, esophageal SCC patients with MCP-1 expression have no favorable prognosis.

Publication types

  • Comparative Study

MeSH terms

  • Angiogenesis Inducing Agents / metabolism
  • Biomarkers, Tumor / metabolism*
  • Biopsy, Needle
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality*
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / surgery
  • Cell Movement
  • Chemokine CCL2 / metabolism*
  • Cohort Studies
  • Culture Techniques
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / mortality*
  • Esophageal Neoplasms / pathology*
  • Esophageal Neoplasms / surgery
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Japan / epidemiology
  • Macrophages / physiology
  • Male
  • Neoplasm Staging
  • Predictive Value of Tests
  • Probability
  • Prognosis
  • Proportional Hazards Models
  • Retrospective Studies
  • Risk Assessment
  • Statistics, Nonparametric
  • Survival Analysis


  • Angiogenesis Inducing Agents
  • Biomarkers, Tumor
  • Chemokine CCL2