Chemokine Binding Protein Ccx-the Ckr In Human Breast Cancer Growth, Metastasis Effects And Mechanisms Of Recurrence

Purpose:The biological axes of chemokines and chcmokine receptors,such as CXCR4/CXCL12,CCR7/CCL19(CCL21),CCK9/CCL25 and CXCR5/CXCL13,involve in cancer growth and metastasis.This study is aimed at the potential regulatory role of atypical chemokine binder CCX-CKR,as a scavenger of CCL19,CCL21, CCL25 and CXCL13 in human breast cancer.Method:Detect the constructive and induced expression of CCX-CKR in breast cancer cells;Construct stable CCX-CKR overexpression cell lines (MDA-MB-435/CCX-CKR and MDA-MB-231HM/CCX-CKR) to investigate the cytobiological change and detect the levels of ligands in the supernatant; establish the xenograft model of human breast cancer in BALB/c mouse to record the growth curve of tumor and the lung metastasis and also to measure the MVD and the levels of CCL19,CCL21,CCL25 and CXCL13 in tumors;Select 98 breast cancer tissue samples to examine CCX-CKR expression by Immunohistochemical staining and analyze its correlation with clinic characteristic and cumulative survival.Results:Many breast cancer cells express CCX-CKR differentially,and CCX-CKR can be regulated by cytokines such as IL-1β,TNF-a and IFN-γ.Overexpression of CCX-CKR inhibited cancer cell proliferation and invasion in vitro and attenuated xenograft tumor growth and lung metastasis in vivo.Lack or low expression of CCX-CKR correlated with a poor survival rate in the breast cancer patients.A significant correlation between CCX-CKR and lymph node metastasis was observed in human breast cancer tissues.CCX-CKR status was an independent prognostic factor for disease free survival(DFS) in the breast cancer patients. CCX-CKR status was an independent prognostic factor for disease free survival (DFS) in the breast cancer patients.Conclusion:We demonstrated for the first time that CCX-CKR is a negative regulator of growth and metastasis in breast cancer,mainly by sequestration of homeostatic chemokines and subsequent inhibition of intratumoral neovascularity.This finding may lead to a new therapeutic strategy against breast cancer.