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Inhibition of CXCR4-Mediated Breast Cancer Metastasis: A Potential Role for Heparinoids?

Authors' Affiliations: ¹ Breast Research Group, School of Surgical and Reproductive Sciences and ² Institute of Cellular Medicine, The Medical School, Newcastle University; and ³ Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

Requests for reprints: John A. Kirby, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom. Phone: 44-191-222-7057; Fax: 44-191-222-7057; E-mail: J.A.Kirby{at}ncl.ac.uk.

Purpose: The pattern of breast cancer metastasis may be determined by interactions between CXCR4 on breast cancer cells and CXCL12 within normal tissues. Glycosaminoglycans bind chemokines for presentation to responsive cells. This study was designed to test the hypothesis that soluble heparinoid glycosaminoglycan molecules can disrupt the normal response to CXCL12, thereby reducing the metastasis of CXCR4-expressing cancer cells.

Experimental Design: Inhibition of the response of CXCR4-expressing Chinese hamster ovary cells to CXCL12 was assessed by measurement of calcium flux and chemotaxis. Radioligand binding was also assessed to quantify the potential of soluble heparinoids to prevent specific receptor ligation. The human breast cancer cell line MDA-MB-231 and a range of sublines were assessed for their sensitivity to heparinoid-mediated inhibition of chemotaxis. A model of hematogenous breast cancer metastasis was established, and the potential of clinically relevant doses of heparinoids to inhibit CXCL12 presentation and metastatic disease was assessed.

Results: Unfractionated heparin and the low-molecular-weight heparin tinzaparin inhibited receptor ligation and the response of CXCR4-expressing Chinese hamster ovary cells and human breast cancer cell lines to CXCL12. Heparin also removed CXCL12 from its normal site of expression on the surface of parenchymal cells in the murine lung. Both heparin and two clinically relevant dose regimens of tinzaparin reduced hematogenous metastatic spread of human breast cancer cells to the lung in a murine model.

Conclusions: Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.

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