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CXCR4 Inhibition Induces Tumor Necrosis by Selectively Targeting the Proliferating Blood Vessels in Oral Squamous
Yamin Soe1, Hotaka Kawai1,2, Htoo Shwe Eain1
1Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, Okayama, 7008558, Japan.
Abstract:
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.
Insights
C-X-C chemokine receptor type 4 (CXCR4) in oral squamous cell carcinoma (OSCC) vasculature correlates with advanced grades. Inhibiting CXCR4 with AMD3100 reduces tumor vessels and induces necrosis, showing therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- C-X-C chemokine receptor type 4 (CXCR4) is a G protein-coupled receptor implicated in tumor growth and metastasis.
- While CXCR4's role in cancer cells is studied, its impact on tumor vasculature is less understood.
- Tumor vascular heterogeneity within the tumor microenvironment (TME) can affect treatment efficacy.
Purpose of the Study:
- To investigate the association between CXCR4 expression in oral squamous cell carcinoma (OSCC) vasculature and pathological grade.
- To explore the therapeutic effects of CXCR4 antagonism on diverse blood vessels within the OSCC tumor stroma.
- To determine if CXCR4 inhibition impacts tumor micro-vessel maturation and TME necrosis.
Main Methods:
- Examined CXCR4 expression in OSCC tumor vasculature and correlated it with pathological grades.
- Utilized AMD3100, a CXCR4 antagonist, to assess its impact on tumor stroma and vasculature.
- Evaluated the overlap of CXCR4 with CD105+ angiogenic vessels and other vascular markers.
- Assessed the effect of AMD3100 on tumor micro-vessel maturation and TME necrosis in an OSCC model.
Main Results:
- CXCR4 expression in tumor vasculature significantly correlated with higher pathological grades in OSCC (p<0.03).
- AMD3100 treatment induced necrosis in the TME of a poorly differentiated OSCC model.
- CXCR4 showed high overlap with CD105+ angiogenic tumor vessels.
- AMD3100 treatment markedly reduced CD105+ vessels and impaired tumor micro-vessel maturation.
Conclusions:
- CXCR4 expression in OSCC vasculature is a potential biomarker for advanced disease.
- CXCR4 antagonism with AMD3100 demonstrates therapeutic potential by targeting tumor vasculature.
- Inhibition of CXCR4 disrupts tumor angiogenesis and maturation, leading to TME necrosis and offering a promising treatment strategy for advanced OSCC.
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