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)