The oxidized-LDL/LOX-1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells
The oxidized-LDL/LOX-1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells
复制标题
DOI：
10.1002/ijc.34134
复制
发表时间：
2022-06-09
影响因子：
6.4
通讯作者：
Hida, Kyoko
中科院分区：
文献类型：
--
作者：
Tsumita, Takuya;Maishi, Nako;Hida, Kyoko
癌症和心血管疾病之间的流行病学关系已有报道，但分子基础仍不清楚。一些与低密度脂蛋白（LDL）紧密结合的蛋白聚糖在动脉粥样硬化区域和高转移性肿瘤组织中都很丰富。低密度脂蛋白的滞留是动脉粥样硬化的关键，虽然它的恶性肿瘤的贡献是未知的。在我们的研究中，我们显示了LDL积累在肿瘤转移中的重要性。我们证明，高转移性肿瘤组织含有大量的LDL，并形成更多的氧化LDL（ox-LDL）。有趣的是，凝集素样氧化低密度脂蛋白受体1（LOX-1），氧化低密度脂蛋白的受体和公认的心血管疾病的关键分子，在肿瘤内皮细胞（TECs）中高度表达。中性粒细胞对ox-LDL的形成很重要。由于我们观察到HM肿瘤中嗜中性粒细胞的积累和活化，我们评估了LOX-1参与嗜中性粒细胞迁移和活化。LOX-1诱导中性粒细胞迁移通过分泌CCL 2从TEC，这是增强ox-LDL。最后，我们发现基因操作LOX-1在TEC或肿瘤间质中的表达倾向于减少肺转移。因此，TEC中的LOX-1/ox-LDL轴可能通过吸引中性粒细胞而导致高转移性肿瘤微环境的形成。
Epidemiological relationships between cancer and cardiovascular diseases have been reported, but a molecular basis remains unclear. Some proteoglycans that strongly bind low-density-lipoprotein (LDL) are abundant both in atherosclerotic regions and in high metastatic-tumor tissue. LDL retention is crucial for the initiation of atherosclerosis, although its contribution to malignancy of cancer is not known. In our study, we show the importance of the accumulation of LDL in tumor metastasis. We demonstrated that high metastatic-tumor tissue contains high amounts of LDL and forms more oxidized LDL (ox-LDL). Interestingly, lectin-like ox-LDL receptor 1 (LOX-1), a receptor for ox-LDL and a recognized key molecule for cardiovascular diseases, was highly expressed in tumor endothelial cells (TECs). Neutrophils are important for ox-LDL formation. Since we observed the accumulation and activation of neutrophils in HM-tumors, we evaluated the involvement of LOX-1 in neutrophil migration and activation. LOX-1 induced neutrophil migration via CCL2 secretion from TECs, which was enhanced by ox-LDL. Finally, we show genetic manipulation of LOX-1 expression in TECs or tumor stroma tended to reduce lung metastasis. Thus, the LOX-1/ox-LDL axis in TECs may lead to the formation of a high metastatic-tumor microenvironment via attracting neutrophils.