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Colorectal Cancer Is Associated With Elevated Plasma Levels of Chitinase 3-Like-1
H M C. Shantha Kumara*1, Hiromichi Miyagaki1,2, Jeanine Arkenbosch1, Xiaohong Yan1, Sonali a. Herath1, Sahani De Silva1, Linda Njoh1, Vesna Cekic1, Richard L. Whelan1
1Division of Colon and Rectal Surgery, Department of Surgery, St Lukes Roosevelt Hospital Center, New York, NY; 2Department of Gastroenterological Surgery, Graduate school of Medicine, Osaka University,2-2, Yamadaoka, Suita,, Osaka, Japan
Introduction: Chitinase 3-Like1 (CHI3L1) is a secreted heparin binding glycoprotein expressed in many cell types including immune cells, endothelium and cancer cells. CHI3L1 enhances macrophage chemotaxis into cancers and macrophage production of IL8 and MCP-1 in the tumor microenvironment which promotes tumor angeogenesis and progression. CHI3L1 also regulates cellular and tissue responses via IL-13 receptor alpha 2 and promotes in vitro cancer cell proliferation, human endothelial cell migration and tubule formation. CHI3L1 expression has been noted in gliblastoma, colon, breast, and hepatocellular carcinomas and increased blood levels of CHI3L1 have been noted in patients with breast, lung, ovarian and prostate cancers. Blood levels in the setting of colorectal cancer (CRC) have not been well studied. This study's purpose was to compare preoperative (PreOp) plasma CHI3L1 levels in CRC and benign colonic pathology (BCP) patients.
Method: Preoperative (PreOp) plasma samples were obtained from consenting CRC and BCP patients undergoing elective resection. Demographic, clinical, operative and pathologic data were collected. CHI3L1 levels in preop plasma samples were determined via ELISA in duplicate and reported as median + 95%CI (ng/ml). The expression of CHI3L1in self paired CRC specimens with normal tissue of a subpopulation of study patients was assessed by QRT-PCR. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to assess plasma CHI3L1 as a diagnostic tool for CRC. The Mann-Whitney test was used for statistical analysis (significance p<0.05).
Results: A total of 188 CRC (79% colon, 21% rectal) and 78 BCP patients (adenoma 27%, diverticulitis 65%, other 8%) were studied. The male/female ratio's were similar but the CRC patients were older (p<0.001). The CRC stage distribution was: Stage 1, 24%; Stage 2, 37%; Stage 3, 30%; and Stage 4, 9%. The median plasma CHI3L1 levels were significantly higher in the CRC (87.7, CI: 80.5, 106.8) vs. the BCP patients (36.2, CI: 30.3, 43.5; P=< 0.001). Plasma CHI3L1 levels were significantly higher in stage 4 patients vs. stage 1(p= 0.02). The AUC value for ROC curve was 0.806(sensitivity 55%, specificity 96%). All CRC samples (n=28) tested shows elevated expression of CHI3L1vs. paired normal tissue.
Conclusion: The CRC median CHI3L1level was 2.4 (142.3%) times higher than the BCP result and 52% higher in stage 4 vs. stage 1 patients. ROC curve analysis suggests a PreOp plasma CHI3L1 level has potential as a marker for early CRC detection. Higher levels of CHI3L1 in plasma of CRC may be from tumor, stromal or inflammatory cells associated with the cancer. CHI3L1 supports neoangeogenesis and tumor growth at tumor site. Further study with larger populations of control and CRC patients is warranted.
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