PURPOSE: The biological axes of chemokines and chemokine receptors, such as CXCR4/CXCL12, CCR7/CCL19 (CCL21), CCR9/CCL25, and CXCR5/CXCL13, are involved 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. EXPERIMENTAL DESIGN: The role of CCX-CKR in human breast cancer was investigated in cell lines, animal models, and clinical samples. RESULTS: Overexpression of CCX-CKR inhibited cancer cell proliferation and invasion in vitro and attenuated xenograft tumor growth and lung metastasis in vivo. CCX-CKR can be regulated by cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and IFN-gamma. 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 in breast cancer patients. CONCLUSION: We showed 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.
PURPOSE: The biological axes of chemokines and chemokine receptors, such as CXCR4/CXCL12, CCR7/CCL19 (CCL21), CCR9/CCL25, and CXCR5/CXCL13, are involved 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 humanbreast cancer. EXPERIMENTAL DESIGN: The role of CCX-CKR in humanbreast cancer was investigated in cell lines, animal models, and clinical samples. RESULTS: Overexpression of CCX-CKR inhibited cancer cell proliferation and invasion in vitro and attenuated xenograft tumor growth and lung metastasis in vivo. CCX-CKR can be regulated by cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and IFN-gamma. Lack or low expression of CCX-CKR correlated with a poor survival rate in the breast cancerpatients. A significant correlation between CCX-CKR and lymph node metastasis was observed in humanbreast cancer tissues. CCX-CKR status was an independent prognostic factor for disease-free survival in breast cancerpatients. CONCLUSION: We showed 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.
Authors: Anne O Watts; Folkert Verkaar; Miranda M C van der Lee; Claudia A W Timmerman; Martien Kuijer; Jody van Offenbeek; Lambertus H C J van Lith; Martine J Smit; Rob Leurs; Guido J R Zaman; Henry F Vischer Journal: J Biol Chem Date: 2013-01-22 Impact factor: 5.157
Authors: Guido J R Zaman; Martine J Smit; Folkert Verkaar; Jody van Offenbeek; Miranda M C van der Lee; Lambertus H C J van Lith; Anne O Watts; Angelique L W M M Rops; David C Aguilar; Joshua J Ziarek; Johan van der Vlag; Tracy M Handel; Brian F Volkman; Amanda E I Proudfoot; Henry F Vischer Journal: J Immunol Date: 2014-03-17 Impact factor: 5.422
Authors: J Vinet; M van Zwam; I M Dijkstra; N Brouwer; H R J van Weering; A Watts; M Meijer; M R Fokkens; V Kannan; D Verzijl; H F Vischer; M J Smit; R Leurs; K Biber; H W G M Boddeke Journal: Br J Pharmacol Date: 2013-03 Impact factor: 8.739