The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT

Harata-Lee, Yuka, Turvey, Michelle E., Brazzatti, Julie A., Gregor, Carly E., Brown, Michael P., Smyth, Mark J., Comerford, Iain and McColl, Shaun R. (2014) The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT. Immunology and Cell Biology, 92 10: 815-824. doi:10.1038/icb.2014.58


Author Harata-Lee, Yuka
Turvey, Michelle E.
Brazzatti, Julie A.
Gregor, Carly E.
Brown, Michael P.
Smyth, Mark J.
Comerford, Iain
McColl, Shaun R.
Title The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT
Journal name Immunology and Cell Biology   Check publisher's open access policy
ISSN 0818-9641
1440-1711
Publication date 2014-11
Year available 2014
Sub-type Article (original research)
DOI 10.1038/icb.2014.58
Open Access Status
Volume 92
Issue 10
Start page 815
End page 824
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
Formatted abstract
Over the last decade, the significance of the homeostatic CC chemokine receptor-7 and its ligands CC chemokine ligand-19 (CCL19) and CCL21, in various types of cancer, particularly mammary carcinoma, has been highlighted. The chemokine receptor CCX-CKR is a high-affinity receptor for these chemokine ligands but rather than inducing classical downstream signalling events promoting migration, it instead sequesters and targets its ligands for degradation, and appears to function as a regulator of the bioavailability of these chemokines in vivo. Therefore, in this study, we tested the hypothesis that local regulation of chemokine levels by CCX-CKR expressed on tumours alters tumour growth and metastasis in vivo. Expression of CCX-CKR on 4T1.2 mouse mammary carcinoma cells inhibited orthotopic tumour growth. However, this effect could not be correlated with chemokine scavenging in vivo and was not mediated by host adaptive immunity. Conversely, expression of CCX-CKR on 4T1.2 cells resulted in enhanced spontaneous metastasis and haematogenous metastasis in vivo. In vitro characterisation of the tumourigenicity of CCX-CKR-expressing 4T1.2 cells suggested accelerated epithelial–mesenchymal transition (EMT) revealed by their more invasive and motile character, lower adherence to the extracellular matrix and to each other, and greater resistance to anoikis. Further analysis of CCX-CKR-expressing 4T1.2 cells also revealed that transforming growth factor (TGF)-β1 expression was increased both at mRNA and protein levels leading to enhanced autocrine phosphorylation of Smad 2/3 in these cells. Together, our data show a novel function for the chemokine receptor CCX-CKR as a regulator of TGF-β1 expression and the EMT in breast cancer cells.
Keyword Dependent antitumor responses
Chemokine
Breast cancer metastasis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published: NOV-DEC 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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