Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells
Author | Del Molino Del Barrio, Irene |
Author | Meeson, Annette |
Author | Cooke, Katie |
Author | Malki, Mohammed Imad |
Author | Barron-Millar, Ben |
Author | Kirby, John A |
Author | Ali, Simi |
Available date | 2021-09-12T06:04:11Z |
Publication Date | 2022-07-10 |
Publication Name | cancers |
Identifier | http://dx.doi.org/10.3390/cancers13143462 |
Citation | del Molino del Barrio, I.; Meeson, A.; Cooke, K.; Malki, M.I.; Barron-Millar, B.; Kirby, J.A.; Ali, S. Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells. Cancers 2021, 13, 3462. https:// doi.org/10.3390/cancers13143462 |
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 (D103– 134) induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration of PBMCs (p < 0.001) and 4T1-Luc cells (p < 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 g/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 g 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 (p = 0.0148), suggesting the potential to target chemokine binding to HS as a therapeutic option |
Language | en |
Publisher | MDPI |
Subject | CCL21 breast cancer chemokines metastasis |
Type | Article |
Issue Number | 14 |
Volume Number | 13 |
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