Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models.
Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models.
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DOI：
10.18632/oncotarget.12694
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发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Woodward WA
中科院分区：
文献类型：
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作者：
Wolfe AR;Trenton NJ;Debeb BG;Larson R;Ruffell B;Chu K;Hittelman W;Diehl M;Reuben JM;Ueno NT;Woodward WA
炎症性乳腺癌（IBC）是一种独特而致命的疾病，其病因不明。我们假设炎症环境有助于IBC表型。我们使用体外共培养系统来研究正常和极化巨噬细胞（RAW 264.7细胞系）、骨髓源间充质干细胞（MSCs）和IBC细胞（SUM 149和MDA-IBC3）之间的相互作用。我们使用了一个体内模型，通过将IBC细胞与MSCs共同注射到乳腺脂肪垫中来复制IBC表型。然后用巨噬细胞募集抑制剂抗csf1治疗小鼠。MSC和巨噬细胞在共培养中产生更高水平的促肿瘤特性，如增强迁移和升高IL-6分泌。与培养的MSCs共培养的IBC细胞也表现出增强的侵袭和乳腺球形成，并被抗il -6和他汀类药物治疗阻断。IBC细胞和MSCs共注射抗csf1治疗小鼠可抑制肿瘤相关巨噬细胞，抑制肿瘤细胞中pSTAT3的表达。抗csf1治疗的小鼠也表现出肿瘤生长、皮肤侵袭和局部复发的减少。在这里，我们证明了通过IL-6与IBC微环境中发现的细胞的互惠肿瘤相互作用。我们的研究结果表明，IL-6是这些促进肿瘤影响的中介，对IBC诱导的MSCs迁移很重要。
Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti-CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs.