UMR-S949, INSERM, Etablissement Français du Sang-Alsace, Université de Strasbourg, Strasbourg, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
JCI Insight. 2016 Sep 8;1(14):e88245. doi: 10.1172/jci.insight.88245.
Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet α6β1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1 represents a promising target for antimetastatic therapies.
癌细胞的转移扩散导致了 90%的癌症死亡，这是恶性肿瘤的最终标志。越来越多的证据表明，血小板在肿瘤转移中起着主要作用；然而，涉及的分子机制仍不清楚。在这里，我们证明血小板整合素 α6β1 的基因缺失显著降低了实验性和自发性肺转移。体外和体内实验表明，人和鼠血小板 α6β1 支持血小板黏附到各种类型的癌细胞。通过敲低方法，我们确定 ADAM9 是人和鼠肿瘤细胞上 α6β1 的主要反受体。血小板与 DC-9 的静态和流动黏附实验，DC-9 是一种包含 ADAM9 解整合素-半胱氨酸结构域的重组蛋白，表明该受体直接与血小板 α6β1 结合。体内研究表明，血小板 α6β1 与肿瘤细胞表达的 ADAM9 之间的相互作用促进了有效的肺转移。整合素 α6β1 依赖性血小板-肿瘤细胞相互作用诱导血小板活化，并有利于肿瘤细胞的血管外渗过程。最后，我们证明了靶向 α6β1 的药理学方法通过血小板依赖性机制有效抑制肿瘤转移。我们的研究揭示了血小板促进肿瘤转移的机制，并表明整合素 α6β1 是抗转移治疗的一个有前途的靶点。
