SUSD2 promotes tumor-associated macrophage recruitment by increasing levels of MCP-1 in breast cancer.
SUSD2 promotes tumor-associated macrophage recruitment by increasing levels of MCP-1 in breast cancer.
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DOI：
10.1371/journal.pone.0177089
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Egland KA
中科院分区：
文献类型：
--
作者：
Hultgren EM;Patrick ME;Evans RL;Stoos CT;Egland KA
肿瘤相关巨噬细胞（TAM）在肿瘤血管生成中发挥作用，并通过分泌的趋化因子（包括单核细胞趋化蛋白-1（MCP-1/CCL 2））募集到肿瘤微环境（TME）中。需要血管生成来维持增殖并使乳腺癌（BCa）细胞能够转移。了解TAM募集的潜在机制将有助于确定迫切需要的新型药物靶点。Sushi Domain Containing 2（SUSD 2）是BCa细胞上的一种跨膜蛋白，先前在小鼠模型中显示可促进肿瘤血管生成。为了确定SUSD 2在血管生成中的作用，通过免疫组织化学分析对175例人类乳腺肿瘤进行了SUSD 2和巨噬细胞的存在调查。具有高水平SUSD 2染色的肿瘤含有2倍多的TAM，主要是M2促血管生成表型。通过将SC单核细胞分化为SC M0巨噬细胞来开发体外共培养模型系统。与不含SUSD 2的癌细胞相比，当M0巨噬细胞与表达SUSD 2的BCa细胞孵育时，观察到极化的M2巨噬细胞增加2倍。由于已知MCP-1可以招募巨噬细胞，因此比较了表达SUSD 2的MDA-MB-231和MBA-MB-231载体对照细胞系之间的MCP-1水平。与载体对照相比，MCP-1 RNA、细胞内蛋白和分泌的MCP-1均显著增加。SKBR 3中SUSD 2的敲低导致分泌的MCP-1水平显著降低。一致地，与载体对照肿瘤相比，在从体内同基因小鼠模型产生的表达Susd 2的肿瘤中观察到MCP-1水平增加。由于SUSD 2招募巨噬细胞进入TME并促进M2极化，因此抑制SUSD 2的功能可能是乳腺癌患者的有效治疗方法。
Tumor-associated macrophages (TAMs) play a role in tumor angiogenesis and are recruited into the tumor microenvironment (TME) by secreted chemokines, including Monocyte Chemoattractant Protein-1 (MCP-1/CCL2). Angiogenesis is required to sustain proliferation and enable metastasis of breast cancer (BCa) cells. Understanding the underlying mechanisms of TAM recruitment would allow for the identification of desperately needed novel drug targets. Sushi Domain Containing 2 (SUSD2), a transmembrane protein on BCa cells, was previously shown to promote tumor angiogenesis in a murine model. To identify the role of SUSD2 in angiogenesis, 175 human breast tumors were surveyed by immunohistochemical analysis for the presence of SUSD2 and macrophages. Tumors with high levels of SUSD2 staining contained 2-fold more TAMs, mainly of the M2 pro-angiogenic phenotype. An in vitro co-culture model system was developed by differentiating SC monocytes into SC M0 macrophages. A 2-fold increase in polarized M2 macrophages was observed when M0 macrophages were incubated with SUSD2-expressing BCa cells compared to cancer cells that do not contain SUSD2. Since MCP-1 is known to recruit macrophages, levels of MCP-1 were compared between SUSD2-expressing MDA-MB-231 and MBA-MB-231-vector control cell lines. MCP-1 RNA, intracellular protein and secreted MCP-1 were all significantly increased compared to the vector control. Knockdown of SUSD2 in SKBR3 resulted in significantly decreased levels of secreted MCP-1. Consistently, increased levels of MCP-1 were observed in Susd2-expressing tumors generated from an in vivo isogeneic mouse model compared to the vector control tumors. Because SUSD2 recruits macrophages into the TME and promotes M2 polarization, inhibiting the function of SUSD2 may be an effective therapy for breast cancer patients.