Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells
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Date
2022-07-10Author
Del Molino Del Barrio, IreneMeeson, Annette
Cooke, Katie
Malki, Mohammed Imad
Barron-Millar, Ben
Kirby, John A
Ali, Simi
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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
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