Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells



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-.

Access the full-text of this item by clicking on the Open Access link.

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
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