Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer

Yukie Tauchi, Hiroaki Tanaka, Kanako Kumamoto, Mao Tokumoto, Chie Sakimura, Katsunobu Sakurai, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Kazuya Muguruma, Masakazu Yashiro, Kiyoshi Maeda, Masaichi Ohira, Kosei Hirakawa

Research output: Contribution to journalArticle

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Abstract

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 (LECs) derived from lymph nodes (LNs) 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 LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs 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 LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs 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.

Original languageEnglish
Pages (from-to)1101-1109
Number of pages9
JournalCancer Science
Volume107
Issue number8
DOIs
Publication statusPublished - 01-08-2016

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Morphogenesis
Stomach Neoplasms
Endothelial Cells
Macrophages
Lymphangiogenesis
Neoplasms
Coculture Techniques
Lymph Nodes
Matrix Metalloproteinases
Vascular Endothelial Growth Factor C
Gene Expression
Lymphatic Vessels
Macrophage Activation
Intercellular Adhesion Molecule-1
Immunohistochemistry
Cytokines
Neoplasm Metastasis
Inflammation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer. In: Cancer Science. 2016 ; Vol. 107, No. 8. pp. 1101-1109.
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abstract = "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 (LECs) derived from lymph nodes (LNs) 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 LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs 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 LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs 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.",
author = "Yukie Tauchi and Hiroaki Tanaka and Kanako Kumamoto and Mao Tokumoto and Chie Sakimura and Katsunobu Sakurai and Kenjiro Kimura and Takahiro Toyokawa and Ryosuke Amano and Naoshi Kubo and Kazuya Muguruma and Masakazu Yashiro and Kiyoshi Maeda and Masaichi Ohira and Kosei Hirakawa",
year = "2016",
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doi = "10.1111/cas.12977",
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Tauchi, Y, Tanaka, H, Kumamoto, K, Tokumoto, M, Sakimura, C, Sakurai, K, Kimura, K, Toyokawa, T, Amano, R, Kubo, N, Muguruma, K, Yashiro, M, Maeda, K, Ohira, M & Hirakawa, K 2016, 'Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer', Cancer Science, vol. 107, no. 8, pp. 1101-1109. https://doi.org/10.1111/cas.12977

Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer. / 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.

In: Cancer Science, Vol. 107, No. 8, 01.08.2016, p. 1101-1109.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer

AU - Tauchi, Yukie

AU - Tanaka, Hiroaki

AU - Kumamoto, Kanako

AU - Tokumoto, Mao

AU - Sakimura, Chie

AU - Sakurai, Katsunobu

AU - Kimura, Kenjiro

AU - Toyokawa, Takahiro

AU - Amano, Ryosuke

AU - Kubo, Naoshi

AU - Muguruma, Kazuya

AU - Yashiro, Masakazu

AU - Maeda, Kiyoshi

AU - Ohira, Masaichi

AU - Hirakawa, Kosei

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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 (LECs) derived from lymph nodes (LNs) 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 LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs 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 LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs 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.

AB - 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 (LECs) derived from lymph nodes (LNs) 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 LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs 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 LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs 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.

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