Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1.
Xueqian ZhuangHao ZhangXiaoyan LiXiaoxun LiMin CongFangli PengJingyi YuXue ZhangQifeng YangGuo-Hong HuPublished in: Nature cell biology (2017)
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-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.
Keyphrases
- signaling pathway
- stem cells
- cell proliferation
- squamous cell carcinoma
- small cell lung cancer
- clinical trial
- immune response
- bone mineral density
- magnetic resonance imaging
- papillary thyroid
- soft tissue
- bone marrow
- body composition
- postmenopausal women
- drug delivery
- high glucose
- epithelial mesenchymal transition
- endothelial cells
- bone regeneration
- artificial intelligence
- toll like receptor
- cell therapy
- mouse model