title: The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT.
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.
authors.affiliation: Chemokine Biology Laboratory, Centre for Molecular Pathology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Harata-Lee
authors.affiliation: Chemokine Biology Laboratory, Centre for Molecular Pathology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Turvey
authors.affiliation: Chemokine Biology Laboratory, Centre for Molecular Pathology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brazzatti
authors.affiliation: Chemokine Biology Laboratory, Centre for Molecular Pathology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Carly E
authors.initials: CE
authors.lastname: Gregor
authors.affiliation: Experimental Therapeutics Laboratory, Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.affiliation: 1] Immunology in Cancer and Infection Laboratory, Department of Immunology, Queensland Institute of Medical Research, Herston, Queensland, Australia [2] School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Chemokine Biology Laboratory, Centre for Molecular Pathology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.affiliation: Chemokine Biology Laboratory, Centre for Molecular Pathology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018925:Chemokines / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006706:Homeostasis; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D054388:Receptors, CCR / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C000593439:Ackr4 protein, mouse; D018925:Chemokines; D054388:Receptors, CCR; D053773:Transforming Growth Factor beta1