Abstract 672: Plasma levels of Endothelin-1 are increased in colorectal cancer patients versus benign disease patients

Introduction: Endothelin-1 (ET-1) belongs to the Endothelin family and exerts its effects via ETA and ETB receptor (ETAR, ETBR) activation. ET-1 is mainly produced by endothelial cells (EC); its receptors are found in EC and vascular smooth muscle cells. ET-1 increases HIF1α stability and results in transcription of VEGFA, VEGFC, and their receptors. ET-1 has anti-apoptotic effects and influences cell survival pathways, including PI3K-dependent AKT activation and NF-κB signaling that are implicated in tumor progression, migration, and metastatic growth. ETAR inhibition impedes tumor growth and promotes apoptosis. ET-1 is overexpressed in many colorectal cancers. Tumor-derived ET-1 modulates MMP’s and urokinase-type plasminogen activator that facilitate ECM degradation and tumor cell liberation. ET-1 alone also promotes neovascularization. This study assesses and compares preoperative (PreOp) plasma ET-1 levels in colorectal cancer (CRC) and benign colon pathology (BCP) patients. Method: CRC and BCP patients (pts.) undergoing elective colorectal resection who were enrolled in an IRB approved tissue/data bank for whom PreOp plasma samples were available were eligible for the study. Demographic and clinical data were collected. PreOp plasma samples were obtained and stored at -80°C. Plasma ET-1 levels (pg/ml) were determined in duplicate via ELISA in and results presented as median +95% CI. ET-1 expression was analyzed in matched CRC and adjacent normal mucosal tissue samples from a subgroup of CRC patients (n=23) via QRT-PCR. Immunohistochemistry (IHC) was performed on formalin-fixed tissue sections (tumor/normal pairs) as per protocol. Results: A total of 116 CRC pts (68% colon, 32% rectal) and 112 BCD pts (adenoma 46%, diverticulitis 50%, other 4%) were studied. The CRC stage distribution was: Stage (Stg) 1, 30%; Stg 2, 31% Stg 3, 31%; and stg 4,8%. Median plasma ET-1 levels were higher in CRC (1.39, CI: 1.25, 1.56) compared to BCP patients (1.11, CI: 1.021, 1.21p<0.001). A non-significant (ns) increase in mean ET-1 levels were noted in STG IV vs STG I and STG II and STG III was found ( 30-37%) and the mean levels in rectal cancer patients was 21% higher than those found colon cancer pts. IHC validated the presence of ET-1 protein in CRC tumors relative to normal colon. Increased expression of ET-1 was seen in 39% of tested CRC samples (9/23).The AUC value for the ROC curve was 0.673 (sensitivity 53%, specificity 73%). Conclusion: The median plasma level of ET-1 in CRC pts. was 26% greater than noted in BCP pts. Increased tumor expression of ET-1 mRNA was identified in 39% of pts. High expression in the tumor may contribute to the elevated plasma levels. The analysis of the ROC curve indicates that ET-1 could serve as a potential candidate for inclusion in a more comprehensive diagnostic panel with other proteins found to be elevated in CRC pts. Further investigation is necessary. Citation Format: Chandana S. K. Herath Mudiyanselage, Yi-Ru Chen, Neil Mitra, Hiromichi Miyagaki, Elizabeth Nilsson Sjolander, Xiaohong Yan, Vesna Cekic, Richard L. Whelan. Plasma levels of Endothelin-1 are increased in colorectal cancer patients versus benign disease patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 672.