Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination

Gastric Cancer, Dec 2015

Background Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer. Methods The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real-time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect co-culture system in vitro and an in vivo mouse xenograft model. Results The number of peritoneal macrophages with the M2 phenotype (CD68+CD163+ or CD68+CD204+) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-α, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model. Conclusions Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer.

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Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination

Gastric Cancer Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination Takahisa Yamaguchi 0 1 2 3 Sachio Fushida 0 1 2 3 Yasuhiko Yamamoto 0 1 2 3 Tomoya Tsukada 0 1 2 3 Jun Kinoshita 0 1 2 3 Katsunobu Oyama 0 1 2 3 Tomoharu Miyashita 0 1 2 3 Hidehiro Tajima 0 1 2 3 Itasu Ninomiya 0 1 2 3 Seiichi Munesue 0 1 2 3 Ai Harashima 0 1 2 3 Shinichi Harada 0 1 2 3 Hiroshi Yamamoto 0 1 2 3 Tetsuo Ohta 0 1 2 3 0 Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences , Kanazawa , Japan 1 Division of Cancer Medicine, Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences , 13-1 Takara-machi, Kanazawa 920-8641 , Japan 2 & Sachio Fushida 3 Center for Biomedical Research and Education, Kanazawa University Graduate School of Medical Sciences , Kanazawa , Japan Background Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer. Methods The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real-time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect coculture system in vitro and an in vivo mouse xenograft model. Results The number of peritoneal macrophages with the M2 phenotype (CD68?CD163? or CD68?CD204?) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-a, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model. Conclusions Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer. Macrophage; Amphiregulin Introduction Globally, gastric cancer is one of the commonest cancers and a frequent cause of cancer-related deaths [ 1 ]. Peritoneal dissemination is an aggravated type of metastasis in gastric cancer. Although various approaches have been assessed for the treatment of peritoneal dissemination, including systemic chemotherapy, intraperitoneal chemotherapy [ 2, 3 ], extensive intraoperative peritoneal lavage [4], and aggressive surgery [ 5 ], sufficiently satisfactory outcomes have not yet been achieved [ 6, 7 ]; this indicates the need for novel therapeutic strategies. The peritoneal cavity is a large free space in the human body and contains a high number of cells. The connections between tumor cells and their surrounding tumor microenvironment play important roles in tumor initiation and progression. The tumor microenvironment consists of many different kinds of cells, including endothelial cells, fibroblasts, lymphocytes, and macrophages [ 8–11 ]. We have previously reported that human peritoneal mesothelial cells activated by transforming growth factor (TGF)-b1 contribute to tumor progression and fibrosis in gastric cancer [12]. Furthermore, fibrocytes derived from bone marrow play an important role in the microenvironment of tumor sites, enhancing tumor proliferation [ 13 ]. Targeting the tumor microenvironment is essential for controlling tumor development and metastasis. In the present study, we focused on macrophages. Tumor-associated macrophages (TAMs) can be classified into two phenotypes: M1 (classically activated macrophages) and M2 (alternatively activated macrophages). M2 macrophages are oriented toward promoting tumor growth, remodeling tissue, promoting angiogenesis, and suppressing adaptive immunity [ 14, 15 ]. Recently, several studies have reported that the density of M2 macrophages is associated with poor prognosis in patients with glioma, lymphoma, renal cell carcinoma, and intrahepatic cholangiocarcinoma [ 16–19 ]. TAM infiltration into gastric cancer tissue has been found to be positively correlated with the depth of invasion, nodal status, and clinical stage [ 20 ]. However, few reports have described the role of macrophages in the peritoneal dissemination of gastr (...truncated)


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Takahisa Yamaguchi, Sachio Fushida, Yasuhiko Yamamoto, Tomoya Tsukada, Jun Kinoshita, Katsunobu Oyama, Tomoharu Miyashita, Hidehiro Tajima, Itasu Ninomiya, Seiichi Munesue, Ai Harashima, Shinichi Harada, Hiroshi Yamamoto, Tetsuo Ohta. Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination, Gastric Cancer, 2016, pp. 1052-1065, Volume 19, Issue 4, DOI: 10.1007/s10120-015-0579-8