Harvey James R, Mellor Paul, Eldaly Hesham, Lennard Thomas W J, Kirby John A, Ali Simi
Breast Research Group, School of Surgical and Reproductive Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Clin Cancer Res. 2007 Mar 1;13(5):1562-70. doi: 10.1158/1078-0432.CCR-06-1987.
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.
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.
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.
Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.
乳腺癌转移模式可能由乳腺癌细胞上的CXCR4与正常组织中的CXCL12之间的相互作用所决定。糖胺聚糖结合趋化因子以呈递给反应性细胞。本研究旨在检验以下假设：可溶性类肝素糖胺聚糖分子可破坏对CXCL12的正常反应，从而减少表达CXCR4的癌细胞的转移。
通过测量钙流和趋化性来评估表达CXCR4的中国仓鼠卵巢细胞对CXCL12反应的抑制情况。还评估了放射性配体结合，以量化可溶性类肝素预防特异性受体结合的潜力。评估了人乳腺癌细胞系MDA-MB-231及其一系列亚系对类肝素介导的趋化抑制的敏感性。建立了血行性乳腺癌转移模型，并评估了临床相关剂量的类肝素抑制CXCL12呈递和转移性疾病的潜力。
未分级肝素和低分子量肝素替扎肝素抑制受体结合以及表达CXCR4的中国仓鼠卵巢细胞和人乳腺癌细胞系对CXCL12的反应。肝素还从鼠肺实质细胞表面的正常表达位点去除了CXCL12。在鼠模型中，肝素和替扎肝素的两种临床相关剂量方案均减少了人乳腺癌细胞向肺的血行转移扩散。
临床相关浓度的替扎肝素抑制CXCL12与CXCR4之间的相互作用，可能有助于预防趋化因子驱动的乳腺癌转移。
