Chemokine (C-C Motif) Ligand 2 Engages CCR2+ Stromal Cells of Monocytic Origin to Promote Breast Cancer Metastasis to Lung and Bone

Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2009; 284(42):29087-96. DOI: 10.1074/jbc.M109.035899
Source: PubMed


Metastatic spread of cancer to distant vital organs, including lung and bone, is the overwhelming cause of breast cancer mortality and morbidity. Effective treatment of systemic metastasis relies on the identification and functional characterization of metastasis mediators to multiple organs. Overexpression of the chemokine (C-C motif) ligand 2 (CCL2) is frequently associated with advanced tumor stage and metastatic relapse in breast cancer. However, the functional mechanism of CCL2 in promoting organ-specific metastasis of breast cancer has not been rigorously investigated. Here, we used organ-specific metastatic sublines of the MDA-MB-231 human breast cancer cell line to demonstrate that overexpression of CCL2 promotes breast cancer metastasis to both lung and bone. Conversely, blocking CCL2 function with a neutralizing antibody reduced lung and bone metastases. The enhancement of lung and bone metastases by CCL2 was associated with increased macrophage infiltration and osteoclast differentiation, respectively. By performing functional assays with primary cells isolated from the wild type, CCL2 and CCR2 knock-out mice, we showed that tumor cell-derived CCL2 depends on its receptor CCR2 (chemokine, CC motif, receptor 2) expressed on stromal cells to exert its function in promoting macrophage recruitment and osteoclast differentiation. Overall, these data demonstrated that CCL2-expressing breast tumor cells engage CCR2(+) stromal cells of monocytic origin, including macrophages and preosteoclasts, to facilitate colonization in lung and bone. Therefore, CCL2 and CCR2 are promising therapeutic targets for simultaneously inhibiting lung and bone metastasis of breast cancer.

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    • "Especially the involvement of GAGs has so far been underestimated, and its mechanisms in vivo have remained elusive. The mechanism of the dnCCL2-HSA chimera action appears to be different to CCL2-neutralizing antibodies[12,13]. Here, we show that dnCCL2-HSA chimera efficiently accumulates around the metastatic tumors cell in the lungs. "
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    • "Blocking CCL2 in breast cancer cells impedes metastatic seeding, underpinning the role of the CCL2/C-C chemokine receptor type 2 (CCR2) axis in promoting breast cancer metastasis. Breast cancer cells secreting CCL2 induce monocyte-derived CCR2 + stromal cells to assist colonisation in the lung and bone, therefore facilitating metastasis (Lu and Kang, 2009). CCL2 expression is also upregulated in poorly differentiated breast cancers and supports the formation of tumour spheres in vitro, whereas loss of CCL2 delays tumourigenesis in cancer stem cells (CSCs) (Tsuyada et al., 2012). "

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