Research Papers:

CCL2/EGF positive feedback loop between cancer cells and macrophages promotes cell migration and invasion in head and neck squamous cell carcinoma

Lu Gao, Feng-qin Wang, Hui-min Li, Jie-gang Yang, Jian-Gang Ren, Ke-fei He, Bing Liu, Wei Zhang and Yi-Fang Zhao _

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Oncotarget. 2016; 7:87037-87051. https://doi.org/10.18632/oncotarget.13523

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Lu Gao1,3,*, Feng-qin Wang1,4,*, Hui-min Li1, Jie-gang Yang1, Jian-Gang Ren1,2, Ke-fei He1,2, Bing Liu2, Wei Zhang1,2, Yi-Fang Zhao1,2

1The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China

2Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China

3College of Stomatology, Dalian Medical University, Dalian 116044, China

4Department of Stomatology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China

*These authors contributed equally to this work

Correspondence to:

Yi-Fang Zhao, email: [email protected]

Wei Zhang, email: [email protected]

Keywords: HNSCC, tumor associated macrophages, invadopodia, CCL2, EGF

Received: May 07, 2016     Accepted: November 02, 2016     Published: November 23, 2016


Head and neck squamous cell carcinoma (HNSCC) represents the most frequent malignancy in the head and neck region, and the survival rate has not been improved significantly over the past three decades. It has been reported the infiltrated macrophages contribute to the malignant progression of HNSCC. However, the crosstalk between macrophages and cancer cells remains poorly understood. In the present study, we explored interactions between monocytes/macrophages and HNSCC cells by establishing the direct co-culture system, and found that the crosstalk promoted the migration and invasion of cancer cells by enhancing the invadopodia formation through a CCL2/EGF positive feedback loop. Our results demonstrated HNSCC cells educated monocytes into M2-like macrophages by releasing C-C motif chemokine ligand 2 (CCL2, or MCP-1). And the M2-like macrophages secreted epithelial growth factor (EGF), which increased the motility of HNSCC cells by enhancing the invadopodia formation. These subcellular pseudopodia degraded extracellular matrix (ECM), facilitating tumor local invasion and distant metastasis. Moreover, EGF up-regulated CCL2 expression in HNSCC cells, which recruited monocytes and turned them into M2-like macrophages, thus forming a positive feedback paracrine loop. Finally, we reported that curcumin, a powerful natural drug, suppressed the production of EGF and CCL2 in macrophages and cancer cells, respectively, blocking the feedback loop and suppressing the migration and invasion of HNSCC cells. These results shed light on the possibilities and approaches based on targeting the crosstalk between cancer cells and monocytes/macrophages in HNSCC for potential cancer therapy.

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