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

Abstract

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 cellderived 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.Breast cancer is the most common malignancy in women in the United States, with an estimated 182,000 new cases and 40,000 deaths in 2008 (1). Late stage breast cancer patients develop metastases in bone, lung, liver, brain, and other organs, which are responsible for most breast cancer-related mortality and morbidity (2). Severe complications from bone metastasis include debilitating bone fractures, nerve compression and bone pain, and hypercalcemia (3-5), whereas lung metastasis is accompanied by cough, bloody sputum, rib cage pain, and, eventually, failure of the respiratory functions (6). Colonization of different secondary organs by breast cancer is believed to be a complex, multigenic process that depends on productive interactions between tumor cells and stromal microenvironments through concerted actions of organ-specific metastasis genes (7,8). Functional genomic analysis of preclinical models of breast cancer to bone, lung, and brain have identified distinct sets of organ-specific metastasis genes (9 -11), providing novel mechanistic insights into key rate-limiting steps of metastasis to different organs. However, as advanced breast cancer patients often suffer from metastases at several secondary organs, identifying genes that are capable of instigating metastasis to multiple sites may provide the ideal targets for therapeutic interventio...

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

“…Over the past years, accumulating evidence has demonstrated novel roles for chemokines and their receptors in regulating biology of the malignant tumors, including metastasis [2][3][4]. Determination of such a predictive molecular marker that is correlated with lymph node metastasis might be important in elucidating the mechanism of metastasis and aid in the personalized theraphy of breast cancer.…”

Turn Off the IDO: Will Clinical Trials Be Successful?

“…Furthermore, in the present study, Smith and colleagues (7) focused only on IL-6, although they also observed that deletion of Ido1 also blunted MCP-1 levels. It is known that MCP-1 (CCL2), together with CCR2, plays a role in the recruitment of immune cells to the tumor microenvironment and also increases the migration of tumor and stromal cells that express CCR2 (10). Moreover, CCL2 expression by tumor or stromal cells and CCR2 + macrophage infi ltration correlates with poor prognosis and metastasis in human breast cancer (11).…”

Pathways of Metastasizing Intestinal Cancer Cells Revealed: How Will Fighting Metastases at the Site of Cancer Cell Arrest Affect Drug Development?

“…In particular, inflammatory chemokines, such as CCL2 and CCL5, are associated with poor prognosis of breast, pancreas and colon cancer due to metastasis, although the mechanisms of action remain under investigation [14][15][16]. CCL2-and CCL5-mediated recruitment of monocytes has been demonstrated to facilitate metastasis for different cancer types [8,12,17]. Recently, we have demonstrated that CCL2 does not only recruit monocytes to the sites of metastasis but, more importantly, enables cancer cell extravasation [13].…”

“…Depending on the stage, cancer patients display a high number of circulating tumor cells and metastasis, therefore a therapy aimed at preventing cancer cell extravasation may strongly reduce the risk of new metastasis, but may not prevent the development of small, already established ones. Nevertheless, accumulating experimental evidence strongly suggests that the interference in cancer cell communication with the microenvironment (e.g., through CCL2) leads to attenuation of metastasis in a number of animal models [8,13,17,18]. Based on this preclinical evidence, two clinical trials have been initiated, evaluating the safety and efficacy of blocking both CCL2 and CCR2 in metastatic patients [101,102].…”