Disruption of The CXC Chemokine Network in Endometrioid Endometrial Adenocarcinoma: Novel Therapeutic Targets and Prognostic Markers

INTRODUCTION: Endometrioid endometrial adenocarcinoma is one of the most common gynecological cancers in women, with an increasing incidence in recent years. CXC chemokines and their receptors, which play a critical role in regulating immune and angiogenic processes in the tumor microenvironment, are thought to have significant functions in endometrial carcinogenesis.
METHODS: In this study, we comprehensively examined the expression profiles of five CXC chemokines (CXCL9, CXCL10, CXCL11, CXCL4, and CXCL4L1) and three CXCR3 receptor variants (CXCR3A, CXCR3B, and CXCR3-alt) in 50 normal endometrium and 50 endometrioid endometrial adenocarcinoma samples using quantitative real-time PCR and immunohistochemical analyses.
RESULTS: Quantitative real-time PCR analyses revealed significant upregulation of CXCR3A, CXCR3-alt, CXCL9, and CXCL11 in endometrioid endometrial adenocarcinoma, whereas CXCR3B, CXCL10, CXCL4, and CXCL4L1 were downregulated. These findings indicate that the pro-proliferative CXCR3A/CXCR3-alt axis becomes hyperactive in tumor tissue, while the angiostatic CXCR3B axis is suppressed. Furthermore, we observed distinct chemokine correlation patterns in normal endometrium and tumor tissue, suggesting a reorganization of the chemokine network during disease progression. Immunohistochemical analyses confirmed the tissue-level localization and cell-specific expression of these molecules. When integrated with clinical data, certain chemokine expression patterns showed significant correlations with tumor stage and grade. Notably, high CXCR3A and low CXCR3B expression were associated with a more aggressive tumor phenotype and poor prognosis.
DISCUSSION AND CONCLUSION: This study provides a comprehensive view of the disruption of the CXC chemokine network in endometrioid endometrial adenocarcinoma. Our findings demonstrate that these molecules not only play a role in the pathogenesis of the disease but also have potential as prognostic markers and therapeutic targets. Targeting CXCR3 receptor variants and their ligands may lead to the development of novel strategies for endometrial cancer treatment in the future. Further studies should focus on translating these findings into clinical applications and evaluating the therapeutic efficacy of CXC chemokine modulation.