Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1
Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1
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Wnt信号抑制剂DKK1对乳腺癌肺和骨转移的不同影响。
DOI：
10.1038/ncb3613
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发表时间：
2017-10-01
影响因子：
21.3
通讯作者：
Hu, Guohong
中科院分区：
文献类型：
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作者：
Zhuang, Xueqian;Zhang, Hao;Hu, Guohong
转移性癌症是一种全身性疾病，并且转移决定因素可能在不同的靶器官中引起完全不同的效应。在这里，我们表明，肿瘤分泌的DKK 1是乳腺癌转移的向器官性的血清学标志物，并抑制肺转移。DKK 1通过拮抗癌细胞非经典WNT/PCP-RAC 1-JNK信号传导抑制肺转移中PTGS 2诱导的巨噬细胞和中性粒细胞募集在肺中，DKK 1还抑制WNT/Ca 2 +-CaMKII-NF-κ B信号传导并抑制LTBP 1介导的癌细胞TGF-β分泌。相反，DKK 1通过调节成骨细胞的经典WNT信号传导促进乳腺骨转移。重要的是，靶向经典WNT可能不利于转移性癌症的治疗，而针对JNK和TGF-β信号传导的联合治疗有效地防止了肺和骨的转移。因此，DKK 1代表了一类在向器官转移中具有二分作用的Janus面分子，我们的数据为新的抗转移方法提供了理论基础。
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/Ca2+-CaMKII-NF-kappa B signalling and suppresses LTBP1-mediated TGF-beta 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-beta 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.