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Three Protein Combinations Angiogenin, Galectin-3 and Activin-a Improves Sensitivity and Specificity of Plasma Analysis for Colorectal Cancer Detection
H M C. Shantha Kumara*1, Hiromichi Miyagaki1, 2, David J. Gaita1, Xiaohong Yan1, Linda Njoh1, Vesna Cekic1, Nipa Gandhi1, Richard L. Whelan1
1Surgery, St Lukes Roosevelt Hospital Center, New York, NY; 2Department of Surgery, Saiseika Senri Hospital, 1-1-6 Tsukumodai, Suita, Osaka 565-0862, Japan
Introduction: Colorectal cancers (CRC) express Angiogenin (ANG), Galectin-3 (Gal-3) and Activin A (Act-A). The binding of ANG to actin on endothelial cell promote EC migration and angiogenesis. Cellular Gal-3 levels associated with cancer cell invasion, angiogenesis and tumor progression. Act-A act via binding to trans membrane receptors and support cancer cell migration. Blood levels of ANG, Gal-3 and Act-A in colorectal cancer (CRC) have not been well studied. This study's purpose was to measure preoperative (PreOp) plasma ANG, Gal-3 and Act-A levels in CRC and benign pathology (BP) patients (pts.) and to assess the diagnostic efficacy of these proteins alone and together.
Method: CRC or BP pts having bowel resection for whom PreOp plasma was available (from IRB approved tissue bank) were studied. Plasma ANG (ng/ml), Gal-3 and Act-A (pg/ml) levels were analyzed in duplicate via ELISA (results: median + 95%CI). Intergroup levels were compared by the Mann-Whitney test (significant;p <0.05). The plasma receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate single and combined proteins levels.
Results: Plasma from 43 BP (polyp 28%, diverticulitis 56%, other 16%) and 120 CRC (83% colon, 17% rectal) pts. were studied. The CRC stage distribution was: Stage-1, 25%; Stage-2, 37%, Stage-3, 26%, Stage- 4, 12%. Median PreOp proteins levels in CRC pts. were significantly higher than BP levels.[ ANG; 390.9,CI: 373.2,405.5 vs 316.8,CI: 297.5,350.9; Gal-3; 12.0,CI: 10.6,13.8 vs 8.9,CI: 7.2,11.1; Act-A; 369.7 CI:349.2,424.0 vs 277.9 CI: 209.3,346.7;P<0.001). Plasma Act-A levels were significantly higher in the Stage 4 pts. than in the stage 1 group ( p=0.001). The single AUC values from the ROC curve for ANG, Gal-3 and Act-A were 0.719, 0.709 and 0.741 with associated 81%, 47% and 42%. The 3 protein combination improved the AUC (0.856) and specificity (90.7%).
Conclusion: CRC median ANG, Gal-3 and Act-A levels were significantly higher (23%, 35% &33% respectively) than BP levels. Although not proven, we believe the plasma elevations are due to the tumor. Higher levels of ANG, Gal-3 and Act-A in plasma of CRC pts. may be related to the tumor cells, stromal cells, and inflammatory cells surrounding the cancer; these elevated levels may related to neovascularization and inflammation-induced tissue remodeling at tumor sites. The 3 protein combination had improved AUC & specificity vs single protein results and may have value as a diagnostic panel. A larger study is needed.
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