Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1
Nature cell biology, 2017•nature.com
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 …
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 …
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/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.
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