CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma
CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma
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DOI：
10.3390/cancers12020459
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发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
Liu, Ju-Fang
中科院分区：
文献类型：
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作者：
Chao, Chia-Chia;Lee, Chiang-Wen;Liu, Ju-Fang
骨肉瘤是最常见的骨恶性肿瘤，有很高的肺转移的可能性。到目前为止，骨肉瘤肺转移的分子机制还不清楚。最近的观察表明，趋化因子CXCL 1及其受体CXCR 2有助于嗜中性粒细胞归巢到肿瘤微环境中。在这里，我们发现CXCL 1/CXCR 2旁分泌轴是骨肉瘤肺转移的关键。在骨肉瘤的体内肺转移模型中，肺血管表达CXCL 1，骨肉瘤细胞表达CXCR 2受体。CXCR 2在骨肉瘤细胞系中的表达高于正常成骨细胞。临床骨肉瘤标本的免疫组化染色显示，CXCR 2表达与病理分期以及血管细胞粘附分子1（VCAM-1）表达呈正相关。人肺动脉内皮细胞（HPAECs）分泌高水平的CXCL 1促进骨肉瘤细胞的迁移，这是通过上调VCAM-1表达介导的。当HPAECs条件培养基在骨肉瘤细胞中孵育时，我们观察到VCAM-1表达需要CXCR 2受体和FAK/PI 3 K/Akt/NF-κ B信号级联。我们的研究结果阐明了骨肉瘤肺转移的分子机制，并表明CXCL 1/CXCR 2值得在治疗方案中作为靶点。
Osteosarcoma, the most common of all bone malignancies, has a high likelihood of lung metastasis. Up until now, the molecular mechanisms involved in osteosarcomas with lung metastases are not clearly understood. Recent observations have shown that the chemokine CXCL1 and its receptor CXCR2 assist with the homing of neutrophils into the tumor microenvironment. Here, we show that the CXCL1/CXCR2 paracrine axis is crucial for lung metastasis in osteosarcoma. In an in vivo lung metastasis model of osteosarcoma, lung blood vessels expressed CXCL1 and osteosarcoma cells expressed the CXCR2 receptor. CXCR2 expression was higher in osteosarcoma cell lines than in normal osteoblast cells. Immunohistochemistry staining of clinical osteosarcoma specimens revealed positive correlations between CXCR2 expression and pathology stage and also vascular cell adhesion molecule 1 (VCAM-1) expression. High levels of CXCL1 secreted by human pulmonary artery endothelial cells (HPAECs) promoted osteosarcoma cell mobility, which was mediated by the upregulation of VCAM-1 expression. When HPAECs-conditioned media was incubated in osteosarcoma cells, we observed that the CXCR2 receptor and FAK/PI3K/Akt/NF-kappa B signaling cascade were required for VCAM-1 expression. Our findings illustrate a molecular mechanism of lung metastasis in osteosarcoma and indicate that CXCL1/CXCR2 is worth targeting in treatment schemas.