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CD163 Is Required for Protumoral Activation of Macrophages In Published OnlineFirst April 2, 2018; DOI: 10.1158/0008-5472.CAN-17-2011 Cancer Tumor Biology and Immunology Research CD163 Is Required for Protumoral Activation of Macrophages in Human and Murine Sarcoma Daisuke Shiraishi1,2, Yukio Fujiwara1, Hasita Horlad1, Yoichi Saito1, Toyohisa Iriki1, Junko Tsuboki1, Pan Cheng1, Naomi Nakagata3, Hiroshi Mizuta2, Hirofumi Bekki4,5, Yasuharu Nakashima5, Yoshinao Oda5, Motohiro Takeya1, and Yoshihiro Komohara1 Abstract Recent findings have shown the significance of CD163-positive Coculture with WT peritoneal macrophages significantly macrophages in tumor progression, yet there have been few increased proliferation of MCA205 cells but decreased in the studies on the function of CD163 in macrophages. Here, we presence of CD163-deficient macrophages. Production of IL6 uncover the role of CD163 in macrophage activation using and CXCL2 in CD163-deficient macrophages was suppressed in CD163-deficient mice and human samples. We detected CD163 comparison with WT macrophages, and overexpression of CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a in CD163-deficient macrophages induced production of IL6 and high percentage of CD163-positive macrophages was associated CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage- with decreased overall survival and higher histologic grade. We induced proliferation of MCA205 cells. Taken together, our results observed macrophage-induced tumor cell proliferation in cocul- show that CD163 is involved in protumoral activation of macro- tures of human monocyte-derived macrophages and leiomyosar- phages and subsequent development and progression of tumors coma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, in mice and humans. which was abrogated by silencing of CD163. Tumor development Significance: Macrophage CD163-mediated induction of IL6 of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was promotes tumor development and progression in murine and significantly abrogated in comparison with wild-type (WT) mice. human malignant tumors. Cancer Res; 78(12); 3255–66. Ó2018 AACR. Introduction responses, whereas M2-like macrophages promote angiogenesis, immunosuppression, and tumor progression via secreting Host-derived immune cells, fibroblasts, and endothelial cells growth-promoting molecules. Macrophages infiltrating cancer constitute the tumor microenvironment and are known to be tissues are referred to as tumor-associated macrophages (TAM), related to tumor progression, and macrophages are a critical which are closely involved in the development of the tumor population of immune cells that induce tumor cell growth, microenvironment, and heterogeneity of macrophage pheno- angiogenesis, metastasis, and immune suppression (1–3). Macro- types is observed among TAMs in various malignant tumors, phages are suggested to be broadly classified into classically including sarcomas (7–9). Several clinicopathologic studies have activated macrophages (M1/kill macrophages) and alternatively recently demonstrated the significance of TAMs in the growth and activated macrophages (M2/repair macrophages) according to progression of malignant tumors. Notably, a high density of their functions and expression markers (4–6). Many studies using þ CD163 TAMs is found to be positively associated with a worse mouse models have indicated that M1-like macrophages produce prognosis in many malignant tumors (9). However, it remains proinflammatory cytokines that stimulate antitumor immune unclear how CD163 works in the protumoral activation of TAMs. Undifferentiated pleomorphic sarcoma (UPS) is the most 1Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto frequent soft-tissue sarcoma that shows no line of differentiation University, Honjo, Kumamoto, Japan. 2Department of Orthopaedic surgery, (10). It has long been known that large numbers of TAMs are Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, detected in UPS, and UPS was previously referred to as malignant Japan. 3Division of Reproductive Engineering, Center for Animal Resources and fibrous histiocytoma (10). Regarding sarcoma, a high density of 4 Development, Kumamoto University, Honjo, Kumamoto, Japan. Department of TAMs has been found to be a prognostic factor in leiomyosarcoma Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, (11, 12). However, little is known about the significance of TAMs Maidashi, Higashi-ku, Fukuoka, Japan. 5Anatomic Pathology, Graduate School of in UPS. In the present study, we newly found a significant Medical Science, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan. þ correlation between a high density of CD163 TAMs and poor Note: Supplementary data for this article are available at Cancer Research clinical course in patients with UPS. Because CD163 is known to Online (http://cancerres.aacrjournals.org/). be upregulated by Th2-type cytokines, CD163 is also considered a D. Shiraishi and Y. Fujiwara contributed equally to this article. marker for M2/repair or protumor phenotype of macrophages Corresponding Author: Yoshihiro Komohara, Graduate School of Medical (13, 14). Based on this background, CD163 is suggested to be Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, critically involved in the protumor functions of TAMs; however, Kumamoto 860-8556, Japan. Phone: 81-96-373-5095; Fax: 81-96-373-5096; few research studies have investigated the functions of CD163 in E-mail: [email protected] the tumor microenvironment. Therefore, we studied the functions doi: 10.1158/0008-5472.CAN-17-2011 of CD163 in TAMs using an animal model and in vitro coculture Ó2018 American Association for Cancer Research. study in the present study. www.aacrjournals.org 3255 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 2, 2018; DOI: 10.1158/0008-5472.CAN-17-2011 Shiraishi et al. Materials and Methods Coculture and 5-bromo-20-deoxyuridine incorporation assay Tumor cells (10,000 cells/well) and macrophages (10,000 Patients and assessment of CD163-positive TAMs cells/well) were directly cocultured in 96-well plates for 2 days. We evaluated 62 tumors diagnosed as UPS that were registered 5-bromo-2'-deoxyuridine (BrdUrd) incorporation was assayed in the Department of Anatomic Pathology, Kyushu University using a BrdUrd Cell Proliferation Kit (Roche) according to the (Fukuoka, Japan), and in the Department of Cell Pathology, manufacturer's protocol. Kumamoto University (Kumamoto, Japan). All samples were primary cases, and radiation-induced sarcomas and secondary sarcomas after chemotherapy were excluded. The reassessed diag- Cell proliferation assay nosis of UPS was made according to the World Health Organi- Briefly, 10,000 tumor cells were cultured in a 96-well plate in zation (WHO) 2013 classification (10). A study using this set of quadruplicate before treatment. The cells were then cultured in UPS cases was previously published (15). We evaluated the extent the presence of IL6 or CXCL2. Cell viability was determined using of necrosis and mitosis to define each tumor's French Federation a WST assay (WST-8 cell counting kit; Dojin Chemical) according of Cancer Centers (FNCLCC) grade. The seventh edition of the to the manufacturer's protocol. American Joint Committee on Cancer (AJCC) staging system was applied to every case. The Institutional Review Board at Kyushu Cytokine array University and Kumamoto University approved this retrospective Cytokine array analysis was performed using a mouse cytokine study (#27-78 and #1175). Immunohistochemistry of Iba1, array kit, panel A (R&D Systems), according to the manufacturer's CD68, and CD163 was performed as described in a previous protocol. study (16). Iba1- and CD163-positive cells were counted in 10 fi randomly selected areas of high-power eld of a microscope by Akt signaling array two pathologists who were blinded to information about the Akt signaling array analysis was performed using a PathScan Akt patients' backgrounds or their prognosis. Signaling Antibody Array Kit (Cell Signaling Technology), accord- ing to the manufacturer's protocol. Tumor cell lines MCA205 (mouse fibrosarcoma of C57BL background), NMFH- Animal studies 1 (human UPS), HT-1080 (human fibrosarcoma), TYLMS-1 All animal experiments have been conducted in accordance (human leiomyosarcoma), and LM8 (mouse osteosarcoma; with an Institutional Animal Care and Use Committee. CD163- À À ref. 17) were purchased from RIKEN Cell Bank or JCRB Cell Bank deficient (CD163 / ) mice in the C57BL/6N background were between 2014 and 2017. Cells were maintained in RPMI 1640 or obtained from the Knockout Mouse Project, and wild-type (WT) DMEM/Ham's F-12 (WAKO) supplemented with 10% fetal mice in the C57BL/6N or C3H background were obtained from À À bovine serum (FBS) and were regularly tested using a Mycoplasma CLEA Japan. CD163 / mice were backcrossed to the C3H strain test kit (TAKARA). These cells were cultured for less than 3 months for more than seven generations. Mice were housed in a temper- before reinitiating the cultures and routinely inspecting micro- ature-controlled room with a 12-hour light/dark cycle. During the scopically for a stable phenotype. course of the experiment, we observed no significant difference in À À body weights between CD163 / and wild-type littermate mice. Human macrophages All animal experiments were approved by the Ethics Committee Peripheral blood mononuclear cells were acquired
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