Abstract

Tumor-associated macrophages (TAMs) are known to be involved in the progression, angiogenesis, and motility of various cancers. We previously reported the association between an increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study the roles of TAMs in ESCC, we first exposed peripheral blood monocyte (PBMo)-derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of the expression of the M2 macrophage marker CD204 and the protumorigenic factors interleukin (IL)-10, VEGFA, and MMPs. Next, we compared gene expression profiles between PBMo-derived macrophages stimulated with or without TECM by cDNA microarray and focused on growth differentiation factor 15 (GDF15) among the highly expressed genes including IL-6, IL-8, and CXCL1. Our immunohistochemical study of 70 surgically resected ESCCs revealed that GDF15 was present not only in cancer cells but also in macrophages. The high expression of GDF15 in the ESCCs was significantly correlated with several more malignant phenotypes including vessel invasion, lymph node metastasis, and clinical stages. Patients with high GDF15 expression showed significantly poorer disease-free survival (P=0.011) and overall survival (P=0.041). We also found that recombinant human GDF15 promotes cell proliferation and the phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in the tumor microenvironment and is associated with aberrant growth and a poor prognosis in human ESCC.

Highlights

  • Tumor microenvironments are composed of neoplastic cells, extracellular matrix, nonmalignant resident stromal cells such as activated fibroblasts, and migratory hemopoietic cells such as macrophages.[1]

  • Conditioned Media of esophageal squamous cell carcinomas (ESCCs) Cell Lines Induced M2-Like Characteristics in peripheral blood monocyte (PBMo)-Derived Macrophages We first investigated the expression levels of M2 markers in PBMo-derived macrophages stimulated with 50% TECM for 2 days in vitro (Figure 1a)

  • The quantitative RT-PCR and immunofluorescence showed that the expression of both CD163 and CD204 in PBMo-derived macrophages stimulated with TECM were significantly more enhanced than in PBMo-derived macrophages (Po0.05; Figures 1c and d)

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Summary

Introduction

Tumor microenvironments are composed of neoplastic cells, extracellular matrix, nonmalignant resident stromal cells such as activated fibroblasts, and migratory hemopoietic cells such as macrophages.[1]. Tumor-associated macrophages (TAMs) are recruited mostly from bone marrow-derived circulating monocytes and they polarize into the M2 or M1/M2 mixed phenotype depending on the microenvironmental factors.[4] In many cancers, TAMs acquire the M2-like phenotype with IL-10high, IL-12low, cell surface expression of mannose receptors, and scavenger receptors such as CD163 and CD204.4,5 In addition, infiltrating TAMs are reported to correlate with poor prognosis by promoting tumor cell growth, invasion angiogenesis, metastasis formation, and immune suppression.[6,7]. We previously described that the number of infiltrating CD204+ macrophages showed a significant correlation with clinicopathological factors and the prognosis of human ESCC, and that a conditioned medium of the TE series ESCC cell line (TECM) induced CD204 and VEGFA expressions in a differentiated THP-1 human acute monocytic leukemia cell line.[15] These observations suggested to us that TAMs, mainly expressing CD204, may contribute to the progression of ESCCs whose tumor microenvironment might induce the specific differentiation of macrophages recruited from circulating bone marrow-derived peripheral blood monocytes (PBMos). We further investigated the specific cancerassociated gene expression profile in TECM-induced TAM-like macrophages by conducting a cDNA microarray analysis

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