The atypical chemokine receptor CCX‐CKR regulates metastasis of mammary carcinoma via an effect on EMT
Autor: | Carly E. Gregor, Julie A. Brazzatti, Michelle E Turvey, Mark J. Smyth, Iain Comerford, Michael P. Brown, Shaun R. McColl, Yuka Harata-Lee |
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Rok vydání: | 2014 |
Předmět: |
Epithelial-Mesenchymal Transition
Chemokine receptor CCR5 Immunology C-C chemokine receptor type 6 Adaptive Immunity Transforming Growth Factor beta1 Mice Receptors CCR Chemokine receptor Animals Homeostasis Immunology and Allergy CCL17 Neoplasm Metastasis biology Carcinoma Mammary Neoplasms Experimental Cell Biology CXCL2 biology.protein Cancer research XCL2 Female Chemokines CC chemokine receptors CCL21 |
Zdroj: | Immunology & Cell Biology. 92:815-824 |
ISSN: | 1440-1711 0818-9641 |
Popis: | 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. |
Databáze: | OpenAIRE |
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