CHITINASE 3-LIKE-1 PROTEIN, OSTEOPONTIN AND MATRIX METALLOPROTEINASE 2 PLASMA LEVELS ARE SIGNIFICANTLY ELEVATED IN COLORECTAL CANCER (CRC) PATIENTS; CONSIDERED TOGETHER THE 3 PROTEINS IMPROVE THE SENSITIVITY/SPECIFICITY OF PLASMA ANALYSIS FOR DIAGNOSIS
Hmc Shantha Kumara*1, Xiaohong Yan1,2, Neil Mitra1, Hansani N. Angammana1, Hiromichi Miyagaki3, Yanni Hedjar1, Vesna Cekic1, Jennifer L. Agnew1, Richard L. Whelan1
1Surgery, Lenox Hill Hospital, Northwell Health, New York, NY; 2Columbia University, New York, NY; 3Department of Surgery, Osaka Rousai Hospital, Osaka, Sakai-shi, Japan
Introduction: Chitinase 3-Like1 (CHI3L1) is a heparin binding protein expressed by immune, endothelial, and cancer cells that promotes tumor angiogenesis and progression. Matrix Metalloproteinase 2 (MMP 2) is a zinc-dependent enzyme that degrades type IV collagen and plays a role in tissue remodeling/wound healing, tumor angiogenesis and cancer growth. Osteopontin (OPN) is an integrin binding phosphorylated glycoprotein secreted by macrophages and leukocytes that plays a role in cell-mediated immunity, inflammation, tumor progression, and cell survival. Over-expression of CHI3L1, MMP2 and OPN has been found in a variety of cancers and has been linked, in some, to tumor progression and prognosis. This study's aim was to compare preoperative (preop) plasma levels of CHI3L1, MMP2 OPN in CRC and benign colonic disease (BCD) patients (pts), alone and in combination, perhaps, as a way to detect CRC.
Methods: Preop plasma samples from CRC and BCD pts undergoing elective resection enrolled in an IRB approved tissue/data bank were studied. Plasma levels of CHI3L1, MMP2 and OPN were determined in duplicate via ELISA (ng/ml) and reported as median + 95%CI. In a subgroup, expression of the 3 proteins were determined in tumor and normal tissues by QRT-PCR. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to assess the diagnostic value of single and multiple plasma protein levels (Mann-Whitney test was for statistical analysis, significance p<0.05).
Results: A total of 156 CRC (73% colon, 27% rectal) and 102 BCP patients (adenoma 32%, diverticulitis 56%, other 12%) were studied; CRC pts were older (p<0.001). The CRC Stage (S) distribution was: S-1, 26%; S-2, 33%; S-3, 29%; and S-4 12%. The CRC median plasma protein levels were significantly higher vs. the BCP group results [Chi3L1: 102.8, CI: 81.8, 124.97vs. 36.2, CI; 30.3, 45.9; MMP 2: 203.6, CI: 195.0, 214.5 vs. 160.2, CI: 151.9, 172.0; OPN: 82.3 CI: 75.3, 89.5 vs 59.2, CI: 53.6, 65.3(P<0.001 for all). Plasma OPN levels were higher in the STG 4 pts. vs STG 1 and STG II group (p<0.01). CRC mRNA overexpression was noted for CHI3L1 (92%), MMP2 (50%) and OPN (77%). The ROC curve AUC value for Chi3L1, MMP2 and OPN were 0.7699, 0.7279 and 0.7329 respectively with 71%, 70% and 61% specificity and 74%, 69% and 75% sensitivity. The AUC for the 3 protein combination was 0.815 with 76% specificity 74% sensitivity.
Conclusion: Median CHI3l1, MMP2 and OPN levels in CRC were significantly higher (183.7%, 27% & 39% respectively) vs BCP levels. Elevated PGRN and OPN levels may promote VEGF mediated vascular invasion and tumor progression while elevated MMP2 may support circulating tumor cell invasion. The combination of three vs single protein AUC results were improved and may have value as a diagnostic panel together with other CRC promoting proteins. Larger studies are warranted.
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