Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop
Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop
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中性粒细胞通过透明质酸介导的 TLR4/PI3K 激活环促进癌细胞的运动
DOI：
10.1002/path.2947
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发表时间：
2011-11-01
影响因子：
7.3
通讯作者：
Kuang, Dong-Ming
中科院分区：
文献类型：
--
作者：
Wu, Yan;Zhao, Qiyi;Kuang, Dong-Ming
炎症是肿瘤进展机制的组成部分。中性粒细胞是许多肿瘤中常见的炎性浸润，但其在瘤形成中的调节和功能尚不清楚。我们最近证实，促炎性IL-17产生细胞通过上皮来源的CXC趋化因子将血液中性粒细胞募集到肝细胞癌的瘤周基质中。在这里，我们表明，大量的中性粒细胞聚集在肝细胞癌，宫颈癌，结直肠癌和胃癌的瘤周基质中，这与肝细胞癌和胃癌的转移有关。中性粒细胞暴露于几种类型的实体瘤细胞（TSN）的培养上清液导致细胞的持续存活和促肿瘤发生作用。动力学实验表明，暴露于TSN后不久，中性粒细胞开始引起激活，然后产生显着的炎性细胞因子，并表达更多的抗凋亡Mcl-1，但较少促凋亡Bax。这些长寿命的中性粒细胞通过接触依赖性机制有效地增强了癌细胞的运动性;这种作用以及暴露于TSN的中性粒细胞的早期激活和随后的寿命可以通过阻断中性粒细胞中PI 3 K/Akt信号传导的激活来逆转。此外，我们发现透明质酸（HA）片段构成了由各种肿瘤产生的共同因子，其模拟TSN诱导长寿命中性粒细胞和随后的恶性细胞迁移的作用。TSN的作用被HA及其受体TLR 4对中性粒细胞的功能阻断相互作用所抑制，表明这是一个关键的信号通路。这些结果表明，来自恶性细胞的HA教育中性粒细胞采用活化表型，并以这种方式刺激恶性细胞的转移，这代表了肿瘤进展期间肿瘤与其基质之间的正调控环。版权所有. (C)2011年英国和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Inflammation is a component of tumour progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumours, but their regulation and functions in neoplasia are not understood. We recently demonstrated that pro-inflammatory IL-17-producing cells recruited blood neutrophils into the peritumoural stroma of hepatocellular carcinoma by epithelium-derived CXC chemokines. Here we show that a substantial population of neutrophils accumulates in the peritumoural stroma of hepatocellular, cervical, colorectal, and gastric carcinomas, and that this correlates with metastases in hepatocellular and gastric carcinomas. Exposure of neutrophils to culture supernatants from several types of solid tumour cells (TSN) resulted in sustained survival and pro-tumourigenic effects of cells. Kinetic experiments reveal that, shortly after exposure to TSN, neutrophils began to provoke activation and then produced significant inflammatory cytokines and expressed more anti-apoptotic Mcl-1 but less pro-apoptotic Bax. These long-lived neutrophils effectively enhanced the cancer cell motility via a contact-dependent mechanism; this effect, together with early activation and subsequent longevity of TSN-exposed neutrophils, could be reversed by blocking the activation of PI3K/Akt signalling in neutrophils. Moreover, we found that hyaluronan (HA) fragments constitute a common factor produced by various tumours that mimics the effect of TSN to induce long-lived neutrophils and subsequent malignant cell migration. The effects of TSN were inhibited by function blocking interactions between HA and its receptor TLR4 on neutrophils, suggesting that this is a key signalling pathway involved. These results indicate that HA derived from malignant cells educates neutrophils to adopt an activated phenotype, and in that way stimulates the metastasis of malignant cells, which represents a positive regulatory loop between tumours and their stroma during neoplastic progression. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.