CXCR4 Inhibition Induces Tumor Necrosis by Selectively Targeting the Proliferating Blood Vessels in Oral Squamous Cell Carcinoma

The C-X-C chemokine receptor type 4 (CXCR4) is a G protein-coupled transmembrane receptor that contributes to tumor growth and angiogenesis. While prior studies have primarily focused on CXCR4 expression in cancer cells and its role in metastasis, a few have examined its involvement in tumor-associated vasculature. In this study, we reported for the first time that CXCR4 expression within the tumor vasculature is significantly associated with higher pathological grades of human oral squamous cell carcinoma (OSCC) (p<0.03). A previous study reported that inhibiting CXCR4 with AMD3100 induces tumor cell death and enhances the efficacy of the chemotherapeutic agent cisplatin. These findings suggest that CXCR4 is an important target for cancer treatment. However, the tumor vascular system is known to be heterogeneous within the tumor microenvironment (TME), which may influence the treatment outcomes. Therefore, this study aimed to explore the effect of CXCR4 antagonism on various blood vessels present within the oral squamous cell carcinoma (OSCC) tumor stroma. Although the efficiency of AMD3100 was not significant in MOC cancer cells, necrosis was induced in the TME when applied to a poorly differentiated OSCC model, highlighting the role of the TME. Notably, CXCR4 is found to be highly overlapped with CD105+ angiogenic tumor vessels among various vascular markers. Treatment with AMD3100 leads to a marked reduction in the CD105+ vessels and impairs the maturation of tumor micro-vessels, explaining the cause of observed necrosis. Thus, CXCR4 serves as a promising biomarker in OSCC, and its inhibition with AMD3100 offers the therapeutic potential, particularly in cases with advanced pathological grades.