Tumor associated macrophage expressing CD204 is associated with tumor aggressiveness of esophageal squamous cell carcinoma

Abstract

Tumor associated macrophages (TAMs) are the most abundant cancer stromal cells educated by tumor microenvironment to acquire trophic functions facilitating angiogenesis, matrix breakdown and cancer cell motility. Tumor associated macrophages have anti-inflammatory properties or "alternatively" activated (M2) phenotype expressing CD204 and ⁄ or CD163. To know the role of TAMs in the growth and progression of esophageal squamous cell carcinomas (ESCCs), we calculated intratumoral CD204, CD163 or CD68 expressing macrophage count (M/C) and CD34-positive microvessel density (MVD) by immunohistochemistry in 70 cases of surgically resected ESCCs and compared them with the clinicopathological factors and prognosis of patients. M/C had positive linear association with MVD. High CD204 + M/C were significantly correlated with more malignant phenotypes including depth of tumor invasion, lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. On the other hand, CD163+ M/C did not associate with these clinicopathological factors with the exception of depth of tumor invasion and blood vessel invasion. Patients with high CD204 + M/C ESCCs showed poor disease-free survival (P = 0.021). Conditioned media of five ESCC cell lines (TE-8, -9, -10, -11 and -15) induced mRNA as well as protein expression of CD204 but not of CD163 with upregulation of vascular endothelial growth factor-A mRNA in TPA treated human acute monocytic leukemia cell line THP-1. These results overall indicate that CD204 is a useful marker for TAMs contributing to the angiogenesis, progression and prognosis of ESCCs whose specific tumor microenvironment may educate macrophages to be CD204

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

“…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). To test our hypothesis, in the present study we exposed PBMo-derived macrophages from healthy volunteers to TECM and observed the cell's acquisition of TAM-like characteristics.…”

“…17,18 Immunohistochemistry Immunohistochemistry was performed with labeled streptavidin biotinylated antibody method as previously described. 15 Specific rabbit polyclonal antibody against growth differentiation factor 15 (GDF15) (HPA011191, 1:50; Sigma-Aldrich, Munich, Germany), specific mouse monoclonal antibodies against CD68 (Kp-1, 1:100; DakoCytomation, Glostrup, Denmark), CD163 (10D6, 1:100; Novocastra, Newcastle upon Tyne, UK), and CD204 (SRA-E5, 1:50; Trans Genic, Kobe, Japan) were used for the primary reaction. For the subsequent reaction, we used labeled streptavidin biotin kit (DakoCytomation).…”

“…CD68 + , CD163 + , and CD204 + cells were counted as macrophages and the estimation was performed as previously described. 15 Evaluation and scoring were performed by three independent observers (authors NU, YK, and HY).…”

Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer

“…In addition, elevated IL4, a marker for M2 tumorassociated macrophages (24), is observed in the plasma of human esophageal SCC patients (25). This macrophage subtype is associated with a more aggressive form of esophageal SCC in humans (26). Because M2 macrophages are generally anti-inflammatory (20), higher numbers in esophageal tissue may inhibit the activity of other killer immune cells, thus preventing immune cell-mediated tumor cell destruction (27).…”

“…Changes in the expression of these cytokines in the plasma and esophagus at the end of the 35-week bioassay were then confirmed using a smaller subset of markers. Cytokine expression was then related to the presence of specific innate immune cells within the esophagus, including macrophages, neutrophils, and natural killer (NK) cells, all of which have been shown to be associated with esophageal SCC progression in humans (26,(31)(32)(33).…”