RRC ID 67711
著者 Urakawa N, Utsunomiya S, Nishio M, Shigeoka M, Takase N, Arai N, Kakeji Y, Koma Y, Yokozaki H.
タイトル GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways.
ジャーナル Lab Invest
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.
巻・号 95(5)
ページ 491-503
公開日 2015-5-1
DOI 10.1038/labinvest.2015.36
PII labinvest201536
PMID 25730371
MeSH Carcinoma, Squamous Cell / metabolism* Cell Line, Tumor Cell Proliferation / drug effects Culture Media, Conditioned / chemistry Culture Media, Conditioned / metabolism Culture Media, Conditioned / pharmacology Cytokines / metabolism Esophageal Neoplasms / metabolism* Esophageal Squamous Cell Carcinoma Growth Differentiation Factor 15 / genetics Growth Differentiation Factor 15 / metabolism* Growth Differentiation Factor 15 / pharmacology* Humans Leukocytes, Mononuclear / drug effects Leukocytes, Mononuclear / metabolism MAP Kinase Signaling System / drug effects* Macrophages / metabolism* Phosphorylation / drug effects Proto-Oncogene Proteins c-akt / metabolism* Tumor Microenvironment / physiology
IF 4.197
リソース情報
ヒト・動物細胞 TE-8(RCB2098) TE-9(RCB1988) TE-15(RCB1951)