Shiraishi D, Fujiwara Y, Horlad H, Saito Y, Iriki T, Tsuboki J, Cheng P, Nakagata N, Mizuta H, Bekki H, Nakashima Y, Oda Y, Takeya M, Komohara Y.
CD163 Is Required for Protumoral Activation of Macrophages in Human and Murine Sarcoma.
Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255-66. ©2018 AACR.
Antigens, CD / genetics
Antigens, CD / immunology
Antigens, CD / metabolism*
Antigens, Differentiation, Myelomonocytic / genetics
Antigens, Differentiation, Myelomonocytic / immunology
Antigens, Differentiation, Myelomonocytic / metabolism*
Cell Line, Tumor / transplantation
Disease Models, Animal
Macrophage Activation / immunology*
Macrophages / immunology*
Macrophages / metabolism
Mice, Inbred C57BL
Receptors, Cell Surface / genetics
Receptors, Cell Surface / immunology
Receptors, Cell Surface / metabolism*
Sarcoma / immunology*
Sarcoma / mortality
Sarcoma / pathology
Tumor Microenvironment / immunology*
|Human and Animal Cells