A preliminary exploration of the role and mechanisms of CD93 in promoting the malignant progression of head and neck squamous cell carcinoma
TL;DR
CD93 may promote HNSCC progression by enhancing tumor-cell aggressiveness and tumor microenvironment remodeling, at least partly through Wnt/β-catenin-related signaling.
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer with an immunosuppressive microenvironment. Although CD93 promotes angiogenesis in tumor endothelial cells, its role in HNSCC tumor cells and the impact of CD93-mediated regulation of tumor cells on the tumor microenvironment are unclear. This study investigates whether CD93 promotes the malignant progression of HNSCC by enhancing tumor cell malignancy and contributing to macrophage-associated and angiogenic remodeling of the tumor microenvironment, elucidating the underlying mechanisms. Methods Bioinformatics analyses assessed CD93 expression, clinical relevance, immune infiltration, and signaling pathways in HNSCC. CD93 expression was validated in clinical specimens and cell lines. CD93 knockdown and overexpression models were used to examine invasion, migration, proliferation, and epithelial–mesenchymal transition (EMT). Conditioned media from CD93-modulated tumor cells were applied to THP-1-derived macrophages and HUVECs to assess macrophage-associated markers and endothelial tube formation. Wnt/β-catenin signaling was pharmacologically activated or inhibited. Xenograft growth and macrophage depletion were evaluated in BALB/c nude mice. Protein–protein docking was used to explore predicted spatial compatibility between CD93 and receptor-proximal Wnt pathway components. Results CD93 was upregulated in HNSCC and associated with poor prognosis and an immunosuppressive, pro-angiogenic TME. CD93 knockdown inhibited invasion, migration, proliferation, EMT-associated changes, CD206 expression, changes in macrophage-associated markers, and endothelial tube formation, whereas CD93 overexpression produced opposite effects. CD93 expression was associated with Wnt/β-catenin activation; CHIR99021 reversed the effects of CD93 knockdown, whereas XAV939 attenuated changes induced by CD93 overexpression. In vivo, CD93 knockdown suppressed xenograft growth, proliferation, angiogenesis, EMT-associated changes, CD206-positive macrophage-associated signals, and β-catenin expression. Clodronate liposome-mediated macrophage depletion reduced HSC3-shNC tumor growth and narrowed the difference between HSC3-shNC and HSC3-shCD93 tumors. Docking analysis indicated that CD93 showed the most favorable predicted spatial compatibility with LRP6 E1E2 among the tested Wnt receptor-related components. Conclusion CD93 may promote HNSCC progression by enhancing tumor-cell aggressiveness and tumor microenvironment remodeling, at least partly through Wnt/β-catenin-related signaling. Docking analysis provides a preliminary structural hypothesis for a potential CD93–LRP6 E1E2 spatial association. CD93 may represent a prognostic biomarker and candidate therapeutic target in HNSCC.