A Positive Feedback Loop Between SPP1+Macrophages and Tumor Cells Promotes Head and Neck Squamous Cell Carcinoma Progression.

Abstract

Background: Emerging research has identified SPP1⁺macrophages as playing a critical role in head and neck squamous cell carcinoma (HNSCC). However, the specific mechanism by which SPP1⁺macrophages promote HNSCC progression remains poorly understood.

Methods: The interaction of SPP1 and CD44 between SPP1⁺macrophages and tumor cells was detected by multiplex immunohistochemical staining of tissue sections, co-immunoprecipitation, and immunocytochemistry after co-culture. Flow cytometry, reverse transcription-polymerase chain reaction, and spheroid-formation assay were used to detect the stemness of tumor cells. Migration ability of tumor cells was analyzed by Transwell and wound-healing assays. In addition, the PI3K/Akt pathway was verified by western blot. The expression of soluble CD44 and SPP1 in serum was detected by enzyme-linked immunosorbent assay, and the expression of SPP1 in macrophages was detected by flow cytometry, western blot, and reverse transcription-polymerase chain reaction.

Results: SPP1 and CD44 formed an interaction between SPP1⁺macrophages and tumor cells in HNSCC. SPP1⁺macrophages released SPP1 to regulate stemness and metastasis characteristics of tumor cells via the SPP1-CD44 axis. Soluble CD44 upregulated SPP1 expression in macrophages and thus, SPP1 and CD44 formed a positive feedback loop between SPP1⁺macrophages and tumor cells in HNSCC.

Conclusions: SPP1-CD44 upregulates stemness and migration abilities of tumor cells in HNSCC. SPP1-CD44 forms an interaction and a positive feedback loop in SPP1⁺macrophages and tumor cells in HNSCC.