The CCL2-CCR2 Axis in Lymph Node Metastasis From Oral Squamous Cell Carcinoma: An Immunohistochemical Study

Abstract

Cytokine or chemokine networks involve lymphatic and distant metastasis of various malignancies, including oral squamous cell carcinoma (OSCC). Immunohistochemical analysis was used to investigate the contribution of the axis of the CC chemokine receptor-2 (CCR2) and the CC chemokine receptor-2 ligand (CCL2) to lymphatic metastasis, particularly the relation between primary OSCC and marginal sinus histiocytosis in regional lymph nodes. Thirteen metastasis-free cases, 15 metastatic cases at resection of primary tumor resection, and 13 postresection metastasis cases were examined. No patient was treated with radiotherapy or chemotherapy before neck dissection. Samples were fixed in formalin, embedded inparaffin, and subjected to immunohistochemical analysis using antibodies against CCL2, CCR2, podoplanin, and α-smooth muscle actin (α-SMA). Marginal sinus histiocytosis was frequently observed in metastatic cases. CCL2 was expressed in tumor-associated neutrophils (TANs) and moderately or poorly differentiated SCC was detected atprimary tumor sites. TANs expressing CCL2 flowed into the marginal sinus in the lymph nodes. CCR2-positive macrophages and mesenchymal cells infiltrated the tumor stroma and were seen within the carcinoma nests. They were predominantly present in the marginal sinus of metastatic cases. In small metastatic foci, α-SMA-positive spindle cells resembling carcinoma-associated fibroblasts (CAFs) were observed adjacent to the macrophages. The CCL2-CCR2 axis is associated with lymphatic metastasis. To clarify the mechanism of lymphatic metastasis from OSCC, further functional analyses of the CCL2-positive TANs, CCR2-positive macrophages, and CAF-like cells detected in this study are recommended.