Most patients with osteosarcoma have subclinical pulmonary micrometastases at diagnosis. Mounting evidence suggests that macrophages facilitate metastasis. As the EGFR has been implicated in carcinoma–macrophage cross-talk, in this study, we asked whether gefitinib, an EGFR inhibitor, reduces osteosarcoma invasion and metastatic outgrowth using the K7M2-Balb/c syngeneic murine model. Macrophages enhanced osteosarcoma invasion in vitro, which was suppressed by gefitinib. Oral gefitinib inhibited tumor extravasation in the lung and reduced the size of metastatic foci, resulting in reduced metastatic burden. Gefitinib also altered pulmonary macrophage phenotype, increasing MHCII and decreasing CD206 expression compared with controls. Surprisingly, these effects are mediated through inhibition of macrophage receptor interacting protein kinase 2 (RIPK2), rather than EGFR. Supporting this, lapatinib, a highly specific EGFR inhibitor that does not inhibit RIPK2, had no effect on macrophage-promoted invasion, and RIPK2−/− macrophages failed to promote invasion. The selective RIPK2 inhibitor WEHI-345 blocked tumor cell invasion in vitro and reduced metastatic burden in vivo. In conclusion, our results indicate that gefitinib blocks macrophage-promoted invasion and metastatic extravasation by reprogramming macrophages through inhibition of RIPK2.

中文翻译：

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吉非替尼通过抑制巨噬细胞受体相互作用丝氨酸/苏氨酸激酶2抑制骨肉瘤的侵袭和转移

大多数骨肉瘤患者在诊断时有亚临床肺微转移。越来越多的证据表明巨噬细胞促进转移。由于 EGFR 与癌 - 巨噬细胞串扰有关，因此在本研究中，我们询问了 EGFR 抑制剂吉非替尼是否使用 K7M2-Balb/c 同系小鼠模型减少骨肉瘤侵袭和转移性生长。巨噬细胞在体外增强骨肉瘤侵袭，这被吉非替尼抑制。口服吉非替尼抑制肿瘤在肺中的外渗并减小转移灶的大小，从而减少转移负担。与对照组相比，吉非替尼还改变了肺巨噬细胞表型，增加了 MHCII 并降低了 CD206 表达。出奇，这些作用是通过抑制巨噬细胞受体相互作用蛋白激酶 2 (RIPK2) 而不是 EGFR 来介导的。支持这一点的是，拉帕替尼（一种不抑制 RIPK2 的高度特异性 EGFR 抑制剂）对巨噬细胞促进的侵袭没有影响，而 RIPK2-/- 巨噬细胞未能促进侵袭。选择性 RIPK2 抑制剂 WEHI-345 在体外阻断肿瘤细胞侵袭并减少体内转移负担。总之，我们的结果表明，吉非替尼通过抑制 RIPK2 重编程巨噬细胞来阻断巨噬细胞促进的侵袭和转移性外渗。选择性 RIPK2 抑制剂 WEHI-345 在体外阻断肿瘤细胞侵袭并减少体内转移负担。总之，我们的结果表明，吉非替尼通过抑制 RIPK2 重编程巨噬细胞来阻断巨噬细胞促进的侵袭和转移性外渗。选择性 RIPK2 抑制剂 WEHI-345 在体外阻断肿瘤细胞侵袭并减少体内转移负担。总之，我们的结果表明，吉非替尼通过抑制 RIPK2 重编程巨噬细胞来阻断巨噬细胞促进的侵袭和转移性外渗。