Del Barrio, Irene Del Molino, Meeson, Annette, Cooke, Katie, Malki, Mohammed Imad, Barron-Millar, Ben, Kirby, John A and Ali, Simi
(2021)
Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells.
CANCERS, 13 (14).
3462-.
Abstract
Chemokine receptor CCR7 is implicated in the metastasis of breast cancer to the lymph nodes. Chemokine function is dependent upon their binding to both cell-surface heparan sulphate (HS) and to their specific receptors; thus, the role of HS in CCR7-mediated lymph node metastasis was investigated by creating a non-HS binding chemokine CCL21 (mut-CCL21). Mut-CCL21 (Δ103-134) induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration of PBMCs (<i>p</i> < 0.001) and 4T1-Luc cells (<i>p</i> < 0.01). Furthermore, the effect of heparin and HS on the chemotactic properties of wild-type (WT) and mut-CCL21 was examined. Interestingly, heparin and HS completely inhibit the chemotaxis mediated by WT-CCL21 at 250 and 500 µg/mL, whereas minimal effect was seen with mut-CCL21. This difference could potentially be attributed to reduced HS binding, as surface plasmon resonance spectroscopy showed that mut-CCL21 did not significantly bind HS compared to WT-CCL21. A murine model was used to assess the potential of mut-CCL21 to prevent lymph node metastasis in vivo. Mice were injected with 4T1-Luc cells in the mammary fat pad and treated daily for a week with 20 µg mut-CCL21. Mice were imaged weekly with IVIS and sacrificed on day 18. Luciferase expression was significantly reduced in lymph nodes from mice that had been treated with mut-CCL21 compared to the control (<i>p</i> = 0.0148), suggesting the potential to target chemokine binding to HS as a therapeutic option.
Item Type: | Article |
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Uncontrolled Keywords: | breast cancer, chemokines, metastasis, CCL21 |
Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
Depositing User: | Symplectic Admin |
Date Deposited: | 02 Aug 2021 10:32 |
Last Modified: | 03 Feb 2024 09:09 |
DOI: | 10.3390/cancers13143462 |
Open Access URL: | https://www.mdpi.com/2072-6694/13/14/3462 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3131085 |