武汉云克隆科技股份有限公司

Abstract: Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP–RAC1–JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2C–CaMKII–NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

摘要：转移癌是一种系统性疾病，在不同的靶标器官中，肿瘤转移的决定因素可能会引起完全不同的效果。我们的研究结果表明肿瘤分泌的DKK1是乳腺癌转移亲器官性的血清学标志物，并可抑制肿瘤的肺转移。在肿瘤的肺转移过程中，DKK1通过对抗癌细胞中非经典的WNT/PCP-RAC1-JNK信号来抑制PTGS2诱导的巨噬细胞和嗜中性粒细胞的招募。在肺中，DKK1还抑制了WNT/Ca2C–CaMKII–NF-κB信号，并抑制了LTBP1介导的癌细胞的TGF-β分泌。与此相反的，DKK1通过调节成骨细胞中经典的WNT信号来促进癌细胞从乳腺到骨的转移。重要的是，靶标经典的WNT可能不利于转移癌的治疗，而对JNK和TGF-β信号的结合治疗可以有效地阻止肿瘤细胞转移到肺和骨头。因此，DKK1在乳腺癌细胞的亲器官性转移过程中发挥着双向的相反的作用，我们的数据为研究新的抗肿瘤转移方法提供了理论依据。

使用试剂原文信息：Serum samples were pre-treated according to the manufacturer’s instructions and analysed with ELISA kits for DKK1 (DKK100, R&D Systems), PGE2 (KGE004B, R&D Systems), DKK2 (SEB033Hu, USCN), DKK3 (ab100502, Abcam) and DKK4 (ab100503, Abcam).