Plasma levels of Serphin-E1 (PAI-1) are significantly increased in patients with colorectal cancer compared to patients with benign colonic disease

Introduction: Plasminogen activator inhibitor-1 (PAI-1), is an inhibitor for urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). PAI-1 has proangiogenic effects and plays a role in epithelial-mesenchymal transition and metastasis. PAI-1 is a modulator of endothelial cell proliferation and migration in vitro and of angiogenesis and tumor growth in vivo. PAI-1 promotes tumor progression by modulating extracellular matrix proteolysis, cellular adhesion, and detachment; it also facilitates invasion/migration of cancer cells. PAI-1 overexpression has been reported in breast and colorectal cancer(CRC). Plasma levels of PAI-1 in CRC patients (pts) have not been well studied. This study's purpose was to compare preoperative (PreOp) plasmaPAI-1 levels in CRC and benign colonic pathology (BCP) patients. Methods: Patients (pts) who underwent colorectal resection for BCP or CRC were prospectively enrolled in an IRB-approved tissue and data bank. Preop blood samples, demographic and clinical data, and pathology results were collected prospectively. Plasma PAI-1 levels were measured in duplicate (ng/ml) using ELISA, with results presented as median ± 95% CI. PAI-1 expression levels were also assessed in paired tumor/normal tissues for a subset of pts using QRT-PCR; immunohistochemistry (IHC) was also carried out on CRC and normal tissue samples. The ROC curve and AUC were used to assess plasma PAI-1 as a CRC diagnostic marker. The Mann-Whitney test was used for statistical analysis (significance p<0.05.) Results: A total of 156 CRC (71%colon, 29%rectal) and 101 BCP pts (adenoma 57%, diverticulitis 32%, other11%) were studied. The Stage (S) breakdown for the CRC group was: S 1, 29%; S 2, 29%; S 3, 36%; and S 4, 6%. The median CRC plasma PAI-1 levels were significantly higher (11.75, CI: 9.06, 15.32) vs. BCP pts (2.95, CI: 2.33, 3.49; P< 0.0001). A non-significant rise in mean PAI-1 levels was observed in Stage II, III, and IV pts compared to S.I (12% - 33%, p=ns). mRNA PAI-1 expression levels were higher (p<0.05) in 50% (9/18) of the CRC tissue samples tested vs. paired normal tissues. IHC confirmed the presence of PAI-1 protein in CRC vs. normal colon tissue. The AUC value for the ROC curve was 0.759 (sensitivity 68%, specificity 77%). Conclusion: The median Preop plasma PAI-1 was 3.9 X higher in the CRC vs. the BCP group. Although not proven, the added PAI-1 found in the plasma of CRC pts is likely produced by tumor cells and the surrounding inflammatory cells. Elevated PAI-1 levels may be related to neovascularization and inflammation-induced tissue remodeling at tumor sites. The AUC results suggest PAI-1 may have value as a CRC prognostic marker in a panel of proteins. Further studies with a larger population of controls and CRC pts are needed to better determine if there is a correlation between plasma PAI-1 levels and cancer stage or progression.