The Mutually Mediated Chloride Intracellular Channel Protein 1 (CLIC1) Relationship between Malignant Cells and Tumor Blood Vessel Endothelium Exhibits a Significant Impact on Tumor Angiogenesis, Progression, and Metastasis in Clear Cell Renal Cell Carcinoma (ccRCC)

SIMPLE SUMMARY: Tumor cells interact with endothelial cells via chloride intracellular channel protein 1 (CLIC1) micro vesicles transfer, inducing endothelial cell proliferation, migration, and tube formation, according to in vitro studies. Furthermore, CLIC1-positive tumor cells appear to have a high invasive and metastasis potential in vitro, but data on human tumor tissues are extremely scarce. CLIC1 expression in tumor blood vessels is reported for the first time here, suggesting CLIC1 as a new endothelial marker. CLIC1 co-expression in tumor and endothelial cells stratified ccRCC cases into several subgroups, and this co-expression influences TNM staging parameters. Based on these findings, we can conclude that CLIC1 is important in angiogenesis, tumor progression, and metastasis in ccRCC. CLIC1 inhibition may have a synergistic effect on tumor cells, as well as tumor vasculature, as our team previously reported for a ccRCC patient-derived tumor xenograft implanted on a chick embryo chorioallantoic membrane treated with anti-CLIC1 antibodies. ABSTRACT: Background: Overexpression of chloride intracellular channel protein 1 (CLIC1) in tumor cells has been confirmed, but it has received less attention in the tumor blood vessel endothelium. Aim: The assessment of CLIC1 expression in ccRCC tumor blood vessels and its relationship with TNM parameters and tumor cell CLIC1 expression. Methods: CLIC1 immunostaining in ccRCC was evaluated in 50 cases in both malignant cells and tumor blood vessels (CLIC1 microvessel density-CLIC1-MVD) and was correlated with TNM staging parameters. Results: CLIC1-MVD was observed in approximately 65% of cases, and CLIC1 co-localization in both tumor and endothelial cells was observed in 59% of cases. ccRCC was classified into four groups (Classes 0–3) based on the percentage of positive tumor cells, with each group including sub-groups defined by CLIC1 expression in the endothelium. Class 3 (60–100% positive tumor cells) had the highest CLIC1-MVD, with an impact on T and M parameters (p value = 0.007 for T, and p value = 0.006 for M). For cases with CLIC1 intracellular translocation, there was a strong correlation between CLIC1-MVD and M (p value < 0.001). Conclusions: Co-expression of ccRCC tumor and endothelial cells promotes tumor progression and metastasis and should be investigated further as a potential therapeutic target for ccRCC and other human malignancies.