Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer.

Jae Moon Gwak,So Yeon Park,Dong Il Kim,An Na Seo,Min Hye Jang,Xin-Yuan Guan

doi:10.1371/journal.pone.0125728

Abstract

Tumor-associated macrophages (TAMs) are involved in tumor progression by promoting epithelial-mesenchymal transition (EMT), tumor cell invasion, migration and angiogenesis. However, in breast cancer, the clinical relevance of the TAM infiltration according to distinct histologic locations (intratumoral vs. stromal) and hormone receptor status is unclear. We investigated the significance of the levels of TAM infiltration in distinct histologic locations in invasive breast cancer. We also examined the relationship of the TAM levels with the clinicopathologic features of tumors, expression of EMT markers, and clinical outcomes. Finally, we analyzed the prognostic value of TAM levels according to hormone receptor status. High levels of infiltration of intratumoral, stromal and total TAMs were associated with high histologic grade, p53 overexpression, high Ki-67 proliferation index and negative hormone receptor status. Infiltration of TAMs was also correlated with overexpression of vimentin, smooth muscle actin and alteration of β-catenin. Overall, a high level of infiltration of intratumoral TAMs was associated with poor disease-free survival, and was found to be an independent prognostic factor. In subgroup analyses by hormone receptor status, a high level of infiltration of intratumoral TAM was an independent prognostic factor in the hormone receptor-positive subgroup, but not in the hormone-receptor negative subgroup. Our findings suggest that intratumoral TAMs play an important role in tumor progression in breast cancer, especially in the hormone receptor-positive group, and the level of TAM infiltration may be used as a prognostic factor and even a therapeutic target in breast cancer.

Highlights

The tumor microenvironment contains a diverse leukocyte population, including neutrophils, eosinophils, dendritic cells, macrophages, mast cells and lymphocytes [1]
As the expression of epithelial-mesenchymal transition (EMT) markers is predominantly found in triple-negative breast cancers [23], we evaluated the association of tumor-associated macrophages (TAMs) infiltration levels with expression of EMT markers in triple-negative breast cancers and non-triple-negative breast cancers
In this study we showed that high levels of infiltration of TAMs in all histological locations were associated with aggressive features of breast cancer and EMT

Summary

Introduction

The tumor microenvironment contains a diverse leukocyte population, including neutrophils, eosinophils, dendritic cells, macrophages, mast cells and lymphocytes [1]. Macrophages are a major component of the leukocyte population, and are among the most important regulators of tumorigenesis [2]. They have the potential to differentiate into either M1- or M2-polarized macrophages, which have opposing effects on tumor progression. Classically-activated M1 macrophages release pro-inflammatory cytokines together with toxic intermediates and activate a type 1 T-cell response that has a cytotoxic effect on tumor cells, whereas M2 macrophages produce proteolytic enzymes, suppress immune activity and contribute to hypoxiainduced angiogenesis, thereby promoting tumor cell proliferation and migration [3,4,5]. TAMs have been regarded as important mediators of tumor progression in breast cancer

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