Abstract
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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers in the world
HNSCC cells educate monocytes into M2polarized macrophages
HNSCCs were closely related with chronic inflammation that was induced by smoking, injury or human papillomavirus (HPV) infection [2]
Summary
Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers in the world. The local recurrence and distant metastases are considered to be the major reasons for the poor prognosis [3]. The underlying mechanisms for the local invasion and distant metastases of HNSCC need to be better understood. The infiltrated macrophages in tumors (termed as tumor associated macrophages, TAMs), as the major inflammatory cellular population in the tumor microenvironment, promote the progression of malignancies by supporting tumor growth, enhancing tumor associated angiogenesis, suppressing adaptive immunity, and assisting tumor cells in invading into surrounding normal tissues and metastasizing to distant organs [6]. Monocytes enter tumor tissues through blood vessels, and differentiate into macrophages under the stimuli from tumor cells or the tumor associated microenvironment [7]. The interactions between monocytes/ macrophages and HNSCC cells, as well as the consequent effects on the progression of HNSCC are largely unknown
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