Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Feng
Lan-Yun
LY
Department of Oncology, Fudan University, Shanghai, People's Republic of China.
Ou
Zhou-Luo
ZL
Wu
Feng-Ying
FY
Shen
Zhen-Zhou
ZZ
Shao
Zhi-Ming
ZM
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000401:mortality / Q000556:secondary; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008207:Lymphatic Metastasis; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054388:Receptors, CCR / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C408223:ACKR4 protein, human; D053583:Interleukin-1beta; D012333:RNA, Messenger; D054388:Receptors, CCR; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma