GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways.
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.
1] Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan [2] Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Naoki
N
Urakawa
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Soken
S
Utsunomiya
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Mari
M
Nishio
1] Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan [2] Division of Oral and Maxillofacial Surgery, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan.
Manabu
M
Shigeoka
1] Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan [2] Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Nobuhisa
N
Takase
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Noriaki
N
Arai
Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Yoshihiro
Y
Kakeji
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Yu-ichiro
Y
Koma
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Hiroshi
H
Yokozaki
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology
D017077:Culture Media, Conditioned; D016207:Cytokines; D055436:Growth Differentiation Factor 15; D051057:Proto-Oncogene Proteins c-akt