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Contribution of heparan sulphate binding in CCL21-mediated migration of breast cancer cells

Lookup NU author(s): Irene del Molino del Barrio, Dr Annette Meeson, Katie Cooke, Dr Imad Malki, Dr Ben Barron-Millar, Emeritus Professor John Kirby, Professor Simi Ali

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.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 (∆103– 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 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 (p = 0.0148), suggesting the potential to target chemokine binding to HS as a therapeutic option.

Publication metadata

Author(s): Del Molino Del Barrio I, Meeson A, Cooke K, Malki MI, Barron-Millar B, Kirby JA, Ali S

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2021

Volume: 13

Issue: 14

Print publication date: 02/07/2021

Online publication date: 10/07/2021

Acceptance date: 02/07/2021

Date deposited: 21/07/2021

ISSN (electronic): 2072-6694

Publisher: MDPI AG

URL: https://doi.org/10.3390/cancers13143462

DOI: 10.3390/cancers13143462

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