Journal Article

Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1

Yu, Jingyi, Zhang, Xue, Li, Xiaoxun, Yang, Qifeng, Hu, Guohong, Zhang, Hao, Peng, Fangli, Zhuang, Xueqian, Cong, Min, Li, Xiaoyan

2017

Overview

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/Ca 2+ –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. Zhuang et al. show that breast-cancer-secreted DKK1, while promoting bone metastases via canonical WNT signalling, inhibits lung metastasis by antagonizing non-canonical Wnt signalling to suppress recruitment of anti-tumour immune cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 13/51 / 45/15 / 631/67/1347 / 631/67/322 / 631/80/86 / 64/60 / Animals / Antineoplastic Agents - pharmacology / Biocompatibility / Biomedical materials / Bone cancer / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - prevention & control / Bone Neoplasms - secondary / Bone tumors / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Ca2+/calmodulin-dependent protein kinase II / Calcium Signaling / Calcium signalling / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / Cancer / Cancer metastasis / Cancer Research / Care and treatment / Cell Biology / Cell Movement - drug effects / Cellular proteins / Complications and side effects / Cyclooxygenase 2 - metabolism / Development and progression / Developmental Biology / Dkk1 protein / Female / Gene expression / Genetic aspects / Health aspects / HeLa Cells / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / JNK Mitogen-Activated Protein Kinases - metabolism / JNK protein / Latent TGF-beta Binding Proteins - metabolism / Life Sciences / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - prevention & control / Lung Neoplasms - secondary / Lungs / Macrophages / Macrophages - metabolism / Macrophages - pathology / Metastases / Metastasis / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Inbred NOD / Mice, SCID / Molecular Targeted Therapy / Neuropeptides - genetics / Neuropeptides - metabolism / Neutrophil Infiltration / Neutrophils - metabolism / Neutrophils - pathology / NF-kappa B - metabolism / Organotropism / Organs / Osteoblasts / Osteoblasts - metabolism / Osteoblasts - pathology / rac1 GTP-Binding Protein - genetics / rac1 GTP-Binding Protein - metabolism / Rac1 protein / Recruitment / RNA Interference / Secretion / Stem Cells / Time Factors / Transfection / Transforming Growth Factor beta1 - metabolism / Tumors / Wnt protein / Wnt Signaling Pathway - drug effects