Open AccessTumor‐associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer
Author(s) -
Tauchi Yukie,
Tanaka Hiroaki,
Kumamoto Kanako,
Tokumoto Mao,
Sakimura Chie,
Sakurai Katsunobu,
Kimura Kenjiro,
Toyokawa Takahiro,
Amano Ryosuke,
Kubo Naoshi,
Muguruma Kazuya,
Yashiro Masakazu,
Maeda Kiyoshi,
Ohira Masaichi,
Hirakawa Kosei
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12977
Subject(s) - lymphangiogenesis , lymphatic endothelium , macrophage , lymphatic system , cancer , pathology , cell adhesion molecule , cancer cell , cancer research , inflammation , tumor progression , biology , microbiology and biotechnology , immunology , medicine , metastasis , in vitro , biochemistry
Tumor lymphangiogenesis is a major prognostic indicator of gastric cancer. Tumor‐induced inflammation has been shown to attract tumor‐associated macrophages that affect lymphangiogenesis. However, detailed mechanisms of macrophage‐induced lymphangiogenesis have not been elucidated. Here, we evaluated the interaction between tumor‐associated macrophages and lymphatic endothelial cells ( LEC s) derived from lymph nodes ( LN s) of human gastric cancer. Lymphatic endothelial cells were directly or indirectly cocultured with macrophages from healthy human blood, with or without the supernatant of the gastric cancer cell line, OCUM ‐12. We analyzed the effect of cancer pretreated macrophages and of macrophages from metastatic LN s of gastric cancer on LEC s. We observed morphological changes of LEC s in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LEC s after contact coculture, and of cancer pretreated macrophages, by quantitative RT ‐ PCR . Specimens of metastatic LN of gastric cancer were immunofluorescently stained. We found that tubulogenesis of LEC s was observed only in the contact coculture model. OCUM ‐12 cells promoted macrophage‐induced tubulogenesis of LEC s. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary‐forming LEC s and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMP s, adhesion molecules, and vascular endothelial growth factor‐C. Blocking of intercellular adhesion molecule‐1 and macrophage activation suppressed tubulogenesis of LEC s. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LEC s and macrophages may be an important initial step of tumor lymphangiogenesis developing LN metastasis. Understanding of its mechanisms could be useful for future therapeutics of gastric cancer.