Cancer Letters

Cancer Letters

Volume 252, Issue 1, 8 July 2007, Pages 86-92
Cancer Letters

CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers

https://doi.org/10.1016/j.canlet.2006.12.012Get rights and content

Abstract

In addition to direct effect on tumor cells, the tumor-promoting activity of CCL2 has been ascribed to its role in chemoattracting tumor-associated macrophages. However it is unclear whether CCL2 also attracts other immune regulatory cells during tumor development. In this study, we confirmed the ubiquitous expression of CCR2 in myeloid suppressor cells (MSCs), a main inducer for tumor immune evasion, and identified that cancer patient-derived CCL2 mediated the migration of MSCs to tumors in vitro, which could be interdicted by antibodies neutralizing CCL2 or blocking CCR2. In mouse tumor model, the adoptively transferred CCR2−/− MSCs could not migrate to either tumor or spleen as efficiently as WT MSCs. The absence of CCL2/CCR2 signaling hindered both MSC migration and MSC-promoted tumor growth. Our data provide evidence that CCL2/CCR2 pathway plays a pivotal role in MSC migration, which is a novel mechanism through which CCL2 promotes tumor growth.

Introduction

Tumors use different evasion strategies to avoid recognition and destruction by immune system. In addition to regulatory T cell (Treg), recent findings highlight another kind of tumor-infiltrating immune suppressive cells, named myeloid suppressor cells (MSCs), which are a heterogeneous population of immature myeloid cells originated from bone marrow [1], [2], [3]. MSCs in mouse are marked by Gr-1 and CD11b or more specifically by Gr-1 and CD115 (M-CSFR) [4]. In human being, MSCs are defined as lineage and HLA-DR cells [5], [6]. Accompanying the growth of tumor, MSCs are strikingly accumulated in the body [2], [7], and promote tumor progression through various mechanisms. However, it is still not clear how MSC accumulation is induced and which signal directs the migration of MSCs from bone marrow to tumor.

Given their versatile properties, various chemokines have been found to display protumor effects by regulating angiogenesis, promoting proliferation and apoptosis-resistance of tumor cells, which favor tumor cell invasion and trafficking in an organ-specific manner, and lead to metastasis [8], [9]. Chemokine (CC motif) ligand 2 (CCL2), also known as monocyte chemotactic protein-1 (MCP-1), has been found in a majority of solid cancer types [9], [10], [11], [12]. Although it is well documented that CCL2 attracts and activates mononuclear cells during inflammation, the role of CCL2 in tumor is still ambiguous due to the conflicting data. Some investigations showed the involvement of CCL2 in host anti-tumor activities [13], whereas others, in animal models and clinical epidemiological studies, revealed its protumor activities [9], suggesting that the effect of CCL2 on tumor needs further investigation. In this study, we identified the pivotal role of CCL2 and its receptor CCR2 in the migration of MSC to tumor, and confirmed the CCL2/CCR2-mediated chemotactic migration of MSC in patients with different tumor types as well as in mouse tumor model.

Section snippets

Patient samples

Tumor samples and blood samples were acquired by surgery from untreated cancer patients, which was approved by the Ethical Committee of the Medical Faculty of Tongji Medical College. Informed consent was obtained from all subjects.

Mice and cell line

BALB/c and C57BL/6 mice were purchased from Center of Medical Experimental Animals of Hubei Province (Wuhan, China) and Center of Experimental Animals of Chinese Academy of Medical Science (Beijing, China), respectively. CCR2−/− C57BL/6 mice were purchased from the

The expressions of chemokine CCL2 and its receptor CCR2 in cancer patients

To identify the candidate chemokine which mediates the migration of myeloid suppressor cells (MSCs) to tumor site, we performed the human chemokine/chemokine receptor specific membrane-based microarray (SuperArray, Frederick, MD) assay using patient’s tumor tissue, and found that CCL2 was the main chemokine expressed in tumor tissues (data not shown). We then determined the expression of CCL2 in patient’s tumors and its receptor CCR2 in MSCs of the corresponding patients by RT-PCR and Western

Discussion

In this report, we provide evidence that the migration of myeloid suppressor cells to tumor is dependent on CCL2/CCR2 pathway. In contrast to the abundant expression of CCR2, other chemokine receptors were detected very weakly on MSCs, such as CCR1 and CCR5, or negatively, such as CXCR4 (data not shown), indicating that other chemokine-mediated pathway might not be very important in the chemotactic migration of MSCs. Nevertheless, it should be pointed out that the exception could be existent.

Acknowledgements

The work was supported by National Development Program (973) For Key Basic Research (2002CB513100) of China and the National Natural Science Foundation of China (No. 30471587).

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This work was supported by National Development Program (973) For Key Basic Research (2002CB513100) of China and the National Natural Science Foundation of China (No. 30471587).

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