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Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41419-020-2438-8 Anna Mary Steitz 1 , Alina Steffes 2 , Florian Finkernagel 1 , Annika Unger 1 , Leah Sommerfeld 1 , Julia M Jansen 3 , Uwe Wagner 3 , Johannes Graumann 4, 5 , Rolf Müller 1 , Silke Reinartz 2
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41419-020-2438-8 Anna Mary Steitz 1 , Alina Steffes 2 , Florian Finkernagel 1 , Annika Unger 1 , Leah Sommerfeld 1 , Julia M Jansen 3 , Uwe Wagner 3 , Johannes Graumann 4, 5 , Rolf Müller 1 , Silke Reinartz 2
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A central and unique aspect of high-grade serous ovarian carcinoma (HGSC) is the extensive transcoelomic spreading of tumor cell via the peritoneal fluid or malignant ascites. We and others identified tumor-associated macrophages (TAM) in the ascites as promoters of metastasis-associated processes like extracellular matrix (ECM) remodeling, tumor cell migration, adhesion, and invasion. The precise mechanisms and mediators involved in these functions of TAM are, however, largely unknown. We observed that HGSC migration is promoted by soluble mediators from ascites-derived TAM, which can be emulated by conditioned medium from monocyte-derived macrophages (MDM) differentiated in ascites to TAM-like asc-MDM. A similar effect was observed with IL-10-induced alternatively activated m2c-MDM but not with LPS/IFNγ-induced inflammatory m1-MDM. These observations provided the basis for deconvolution of the complex TAM secretome by performing comparative secretome analysis of matched triplets of different MDM phenotypes with different pro-migratory properties (asc-MDM, m2c-MDM, m1-MDM). Mass spectrometric analysis identified an overlapping set of nine proteins secreted by both asc-MDM and m2c-MDM, but not by m1-MDM. Of these, three proteins, i.e., transforming growth factor beta-induced (TGFBI) protein, tenascin C (TNC), and fibronectin (FN1), have been associated with migration-related functions. Intriguingly, increased ascites concentrations of TGFBI, TNC, and fibronectin were associated with short progression-free survival. Furthermore, transcriptome and secretome analyses point to TAM as major producers of these proteins, further supporting an essential role for TAM in promoting HGSC progression. Consistent with this hypothesis, we were able to demonstrate that the migration-inducing potential of asc-MDM and m2c-MDM secretomes is inhibited, at least partially, by neutralizing antibodies against TGFBI and TNC or siRNA-mediated silencing of TGFBI expression. In conclusion, the present study provides the first experimental evidence that TAM-derived TGFBI and TNC in ascites promote HGSC progression.
中文翻译：
肿瘤相关巨噬细胞通过分泌转化生长因子β诱导型（TGFBI）和腱生蛋白C促进卵巢癌细胞迁移。
高度浆液性卵巢癌（HGSC）的核心和独特方面是肿瘤细胞通过腹膜液或恶性腹水的广泛跨腔扩散。我们和其他人将腹水中的肿瘤相关巨噬细胞（TAM）鉴定为转移相关过程的促进剂，如细胞外基质（ECM）重塑，肿瘤细胞迁移，粘附和侵袭。然而，TAM的这些功能所涉及的确切机制和介体在很大程度上尚不清楚。我们观察到，HGSC的迁移是由腹水来源的TAM的可溶性介体促进的，它可以由腹水中分化为TAM样的asc-MDM的单核细胞来源的巨噬细胞（MDM）的条件培养基模拟。IL-10诱导的交替激活的m2c-MDM观察到了类似的效果，但LPS /IFNγ诱导的炎症性m1-MDM观察不到。这些观察结果通过对具有不同促迁移特性（asc-MDM，m2c-MDM，m1-MDM）的不同MDM表型的匹配三联体进行比较分泌组分析，为复杂TAM分泌组的解卷积提供了基础。质谱分析确定了asc-MDM和m2c-MDM都分泌的九种蛋白质的重叠集合，而m1-MDM却没有。其中，三种蛋白质，即转化生长因子β诱导（TGFBI）蛋白质，腱糖蛋白C（TNC）和纤连蛋白（FN1）已与迁移相关的功能相关。有趣的是，TGFBI，TNC和纤连蛋白的腹水浓度升高与无进展生存期短有关。此外，转录组和分泌组分析表明TAM是这些蛋白质的主要生产者，进一步支持TAM在促进HGSC进程中的重要作用。与此假设一致，我们能够证明，中和针对TGFBI和TNC的抗体或siRNA介导的TGFBI表达沉默，至少部分抑制了asc-MDM和m2c-MDM分泌组迁移诱导的潜力。总之，本研究提供了第一个实验证据，证明TAM衍生的TGFBI和TNC在腹水中促进HGSC进程。
更新日期：2020-04-24
中文翻译：
肿瘤相关巨噬细胞通过分泌转化生长因子β诱导型（TGFBI）和腱生蛋白C促进卵巢癌细胞迁移。
高度浆液性卵巢癌（HGSC）的核心和独特方面是肿瘤细胞通过腹膜液或恶性腹水的广泛跨腔扩散。我们和其他人将腹水中的肿瘤相关巨噬细胞（TAM）鉴定为转移相关过程的促进剂，如细胞外基质（ECM）重塑，肿瘤细胞迁移，粘附和侵袭。然而，TAM的这些功能所涉及的确切机制和介体在很大程度上尚不清楚。我们观察到，HGSC的迁移是由腹水来源的TAM的可溶性介体促进的，它可以由腹水中分化为TAM样的asc-MDM的单核细胞来源的巨噬细胞（MDM）的条件培养基模拟。IL-10诱导的交替激活的m2c-MDM观察到了类似的效果，但LPS /IFNγ诱导的炎症性m1-MDM观察不到。这些观察结果通过对具有不同促迁移特性（asc-MDM，m2c-MDM，m1-MDM）的不同MDM表型的匹配三联体进行比较分泌组分析，为复杂TAM分泌组的解卷积提供了基础。质谱分析确定了asc-MDM和m2c-MDM都分泌的九种蛋白质的重叠集合，而m1-MDM却没有。其中，三种蛋白质，即转化生长因子β诱导（TGFBI）蛋白质，腱糖蛋白C（TNC）和纤连蛋白（FN1）已与迁移相关的功能相关。有趣的是，TGFBI，TNC和纤连蛋白的腹水浓度升高与无进展生存期短有关。此外，转录组和分泌组分析表明TAM是这些蛋白质的主要生产者，进一步支持TAM在促进HGSC进程中的重要作用。与此假设一致，我们能够证明，中和针对TGFBI和TNC的抗体或siRNA介导的TGFBI表达沉默，至少部分抑制了asc-MDM和m2c-MDM分泌组迁移诱导的潜力。总之，本研究提供了第一个实验证据，证明TAM衍生的TGFBI和TNC在腹水中促进HGSC进程。
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