Role of Platelet C-Type Lectin-Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma
Role of Platelet C-Type Lectin-Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma
复制标题
DOI：
10.1002/jbmr.4045
复制
发表时间：
2020-06-01
影响因子：
6.2
通讯作者：
Haro, Hirotaka
中科院分区：
文献类型：
--
作者：
Ichikawa, Jiro;Ando, Takashi;Haro, Hirotaka
肉瘤癌症患者的总体预后在过去 20 年中几乎没有变化。迫切需要研究这些肿瘤的转移潜力并开发抗转移药物。越来越清楚的是，血小板在癌细胞转移的建立中发挥着重要作用，并且可能成为癌症患者的有用治疗靶点。然而，人们对血小板在肉瘤进展中的作用知之甚少。在这里，我们研究了骨肉瘤进展与血小板功能的关系，以探索抗血小板治疗的可能性。我们发现，与癌细胞类似，podoplanin（也称为 Aggrus）阳性骨肉瘤细胞诱导血小板聚集和激活。施用抗糖蛋白 Ib α（GPIb α，也称为 CD42b）抗体可减少骨肉瘤的肺转移。血小板与骨肉瘤细胞共培养的上清液含有多种生长因子，可促进骨肉瘤细胞在体外的增殖、侵袭和球形形成。此外，肺转移的发展高度依赖于骨肉瘤细胞和血小板之间的直接相互作用。为了探索治疗靶点，我们重点关注骨肉瘤上的足足蛋白与血小板上的 C 型凝集素样受体 (CLEC)-2 之间的相互作用。施用针对 CLEC-2 的消耗性抗体可有效抑制骨肉瘤转移至肺部。我们还分析了原发部位和转移部位患者样本的临床数据。尽管两个部位之间的 GPIb α 表达相似，但与原发部位相比，转移部位的足足蛋白显着增加，并且原发部位的足足蛋白表达水平与患者预后相关。这些发现表明，阻断血小板 CLEC-2 和骨肉瘤足足蛋白之间的相互作用是预防骨肉瘤肺转移的最有前途的治疗策略。 (c) 2020 年美国骨与矿物质研究学会。
The overall prognosis of patients with sarcoma-based cancers has changed little in the last 20 years. There is an urgent need to investigate the metastatic potential of these tumors and to develop anti-metastatic drugs. It is becoming increasingly clear that platelets play an important role in the establishment of metastasis of carcinoma cells and could be a useful therapeutic target for patients with carcinoma. However, little is known about the role of platelets in sarcoma progression. Here, we investigated how osteosarcoma progression relates to platelet function to explore the possibility of anti-platelet therapy. We found that, similar to carcinoma cells, podoplanin (also known as Aggrus)-positive osteosarcoma cells induce platelet aggregation and activation. Administration of anti-glycoprotein Ib alpha (GPIb alpha, also known as CD42b) antibody reduced the lung metastasis of osteosarcoma. The supernatant from platelets cocultured with osteosarcoma cells contained several growth factors and promoted proliferation, invasiveness, and sphere formation of osteosarcoma cells in vitro. In addition, the development of lung metastasis was highly dependent on direct interaction between osteosarcoma cells and platelets. To explore the therapeutic target, we focused on the interactions between podoplanin on osteosarcoma and C-type lectin-like receptor (CLEC)-2 on platelets. The administration of a depleting antibody against CLEC-2 efficiently suppressed osteosarcoma metastasis into the lung. We also analyzed clinical data from patient samples at primary and metastatic sites. Although GPIb alpha expression was similar between the two sites, there was a significant increase in podoplanin at the metastatic site compared to that in the primary site, and the level of podoplanin expression in the primary site correlated with patient prognosis. These findings suggest that blockade of interactions between platelets CLEC-2 and osteosarcoma podoplanin represent the most promising therapeutic strategy for preventing the lung metastasis of osteosarcoma. (c) 2020 American Society for Bone and Mineral Research.