Neutrophil TLR4 and PKR are targets of breast cancer cell glycosaminoglycans and effectors of glycosaminoglycan-induced APRIL secretion.
Neutrophil TLR4 and PKR are targets of breast cancer cell glycosaminoglycans and effectors of glycosaminoglycan-induced APRIL secretion.
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DOI：
10.1038/s41389-018-0058-2
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发表时间：
2018-06-15
期刊：
影响因子：
6.2
通讯作者：
Rosales JL
中科院分区：
文献类型：
--
作者：
Bat-Erdene U;Quan E;Chan K;Lee BM;Matook W;Lee KY;Rosales JL
增殖诱导配体（APRIL）可诱导生存和迁移信号以及肿瘤生长，通常在乳腺癌组织中观察到，但在乳腺癌细胞本身中通常不表达。在这里，我们检查了乳腺癌细胞是否诱导中性粒细胞分泌 APRIL，中性粒细胞经常被招募到乳腺肿瘤微环境中。我们发现乳腺癌细胞确实会刺激中性粒细胞通过其糖胺聚糖分泌 APRIL。耗尽硫酸乙酰肝素或硫酸软骨素糖胺聚糖的乳腺癌细胞失去诱导中性粒细胞分泌APRIL的能力，并且硫酸乙酰肝素和硫酸软骨素可诱导与乳腺癌细胞诱导的分泌相当的分泌。虽然刺激 RNA 激活蛋白激酶 (PKR) 足以诱导中性粒细胞 APRIL 分泌，但乳腺癌细胞糖胺聚糖诱导的分泌需要 PKR 和 Toll 样受体 4 (TLR4)，因为单独和特异性抑制 TLR4 或 PKR 会完全阻止该过程，这表明乳腺癌细胞糖胺聚糖靶向中性粒细胞 TLR4 和 PKR 以触发 APRIL 分泌。因此，除了细胞表面硫酸乙酰肝素在结合 APRIL 从而导致细胞生长中的假定作用之外，我们还证明硫酸乙酰肝素以及硫酸软骨素在促进中性粒细胞分泌 APRIL 方面发挥着新的作用，这可能导致进一步的细胞生长。我们提出，乳腺癌细胞通过硫酸乙酰肝素作为 APRIL 的细胞表面受体或对接分子以及作为诱导中性粒细胞 APRIL 分泌以促进其自身生长的配体的双重作用，利用中性粒细胞募集到肿瘤微环境的优势。
A proliferation-inducing ligand (APRIL), which induces survival and migration signals and tumor growth, is commonly observed in breast cancer tissues but is not often expressed in breast cancer cells themselves. Here, we examined whether breast cancer cells induce APRIL secretion from neutrophils, which are frequently recruited into the breast tumor microenvironment. We found that breast cancer cells do stimulate neutrophils to secrete APRIL through their glycosaminoglycans. Breast cancer cells depleted of heparan sulfate or chondroitin sulfate glycosaminoglycans lose their ability to induce APRIL secretion from neutrophils, and heparan sulfate and chondroitin sulfate can induce secretion that is comparable to that of breast cancer cell-induced secretion. While stimulation of the RNA-activated protein kinase (PKR) is sufficient to induce neutrophil APRIL secretion, both PKR and the toll-like receptor 4 (TLR4) are required for breast cancer cell glycosaminoglycan-induced secretion as separate and specific inhibition of TLR4 or PKR completely prevents the process, suggesting that breast cancer cell glycosaminoglycans target neutrophil TLR4 and PKR to trigger APRIL secretion. Thus, apart from the putative role of cell surface heparan sulfate in binding APRIL that leads to cell growth, we demonstrate that heparan sulfate, as well as chondroitin sulfate plays a novel role in promoting neutrophil secretion of APRIL that could lead to further cell growth. We propose that breast cancer cells take advantage of the neutrophil recruitment to the tumor microenvironment through the dual role of heparan sulfate as cell surface receptor or docking molecule for APRIL and as a ligand that induces neutrophil APRIL secretion to promote their own growth.
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影响因子：
4.7
作者：
Garcia-Castro, Araceli;Zonca, Manuela;Planelles, Lourdes
通讯作者：
Planelles, Lourdes
影响因子：
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作者：
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He, Mei-rong
影响因子：
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Hendriks, J;Planelles, L;Medema, JP
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Medema, JP
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影响因子：
15.3
作者：
Hahne, M;Kataoka, T;Schroter, M;Hofmann, K;Irmler, M;Bodmer, J L;Schneider, P;Bornand, T;Holler, N;French, L E;Sordat, B;Rimoldi, D;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
5.4
作者：
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通讯作者：
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