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

Autor: Xingwang Zhang, Xiaoyan Li, Qifeng Yang, Xiaoxun Li, Guohong Hu, Fangli Peng, Jingyi Yu, Min Cong, Hao Zhang, Xueqian Zhuang
Rok vydání: 2016
Předmět:
musculoskeletal diseases
0301 basic medicine
rac1 GTP-Binding Protein
Lung Neoplasms
Time Factors
Neutrophils
Antineoplastic Agents
Bone Neoplasms
Breast Neoplasms
Mice
SCID
Biology
Transfection
Metastasis
Transforming Growth Factor beta1
03 medical and health sciences
Breast cancer
Cell Movement
Mice
Inbred NOD
medicine
Animals
Humans
Calcium Signaling
Molecular Targeted Therapy
Wnt Signaling Pathway
Mice
Inbred BALB C
Osteoblasts
Macrophages
Neuropeptides
Wnt signaling pathway
JNK Mitogen-Activated Protein Kinases
NF-kappa B
Bone metastasis
Cancer
Cell Biology
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
DKK1
Latent TGF-beta Binding Proteins
Neutrophil Infiltration
Cyclooxygenase 2
Cancer cell
Cancer research
Intercellular Signaling Peptides and Proteins
Female
RNA Interference
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Transforming growth factor
HeLa Cells
Zdroj: Nature cell biology. 19(10)
ISSN: 1476-4679
Popis: 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.
Databáze: OpenAIRE
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