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Plasma Levels of Osteopontin Are Significantly Increased in Patients With Colorectal Cancer
H M C. Shantha Kumara*1, Hiromichi Miyagaki1, 2, Sajith a. Herath1, David J. Gaita1, Xiaohong Yan1, Linda Njoh1, Vesna Cekic1, 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: Osteopontin (OPN), also known as early T lymphocyte activation-1, is an integrin binding phosphorylated glycoprotein that has been implicated in numerous physiological and pathological events including cell-mediated immunity, inflammation, cell survival, and tumor progression. Various forms of CD44 serve as receptors for OPN. OPN is secreted by activated macrophages and leukocytes. Over-expression of OPN has been found in a variety of cancers, including CRC, and is associated with the PI3K/AKT and ERK mediated pathways and VEGF mediated vascular invasion and tumor progression. Plasma levels of OPN in colorectal CRC patients (pts) have not been well studied. This study's purpose was to compare preoperative (PreOp) plasma OPN levels in CRC and benign colonic pathology (BCP) patients.
Method: Preoperative (PreOp) plasma samples were obtained from CRC and BCP pts undergoing elective resection. Clinical, demographic and final pathological data were prospectively collected. Plasma OPN levels were determined via ELISA in duplicate and are reported as median +95%CI (ng/ml). Expression levels were determined in tumors and paired normal tissues of a subpopulation of study patients by QRT-PCR and were correlated with plasma OPN levels (spearmen r). The candidacy of OPN as a diagnostic marker for CRC was validated by the receiver operating characteristic (ROC) curve and by the area under the ROC curve (AUC) results. The Mann-Whitney test was used for statistical analysis, (significance p<0.05).
Results: A total of 152 CRC (69%colon, 31%rectal) and 116 BCP patients (adenoma 33%, diverticulitis 47%, other 20%) were studied. The male/female ratios were similar. The CRC stage distribution was: Stage 1, 27%; Stage 2, 33%; Stage 3, 32%; and Stage 4, 8%. The median plasma OPN levels were significantly higher in the CRC (91.3, CI: 84.9,96.3) vs. the BCP patients (66.8,CI: 61.3,71.1; P=< 0.001). There was some correlation between plasma OPN levels and cancer stage (STG I vs STG II; p=0.012, STG I vs STG III; p=0.025, STG I vs STG IV; p=0.006).
The AUC value for the ROC curve was 0.806 (sensitivity 55%, specificity 96%). Increased expression of OPN was noted in 65% of the CRC tissue samples tested (13/20) vs. paired normal tissue; tissue expression correlated with plasma levels (r2=0.5, p=0.001)
Conclusion: The CRC median OPN level was 37% higher than the BCP result and 25% higher in STG 4 vs. STG 1 patients. In general, plasma OPN levels increased with advancing cancer stage. Tumor OPN expression correlated with PreOp plasma levels. The AUC results suggest OPN may have value as a CRC prognostic marker. The most likely source of the added OPN in the plasma is the tumor itself. Further study with larger populations of control and CRC pts is warranted.
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