| Pancreatic carcinoma is one of the most lethal and challenging human solid tumors, which is the seventh leading cause of carcinoma-related deaths worldwide. In the United States, it has been ranked as the fourth leading cause of carcinoma-related deaths, with an average 5-year relative survival rate of about 7%. Tumor infiltration and metastasis are the important biologic characters of pancreatic carcinoma, occurring in early stage of the disease, causing the reduction of survival time of the patients. The degradation of extracellular matrix (ECM) is an essential event during tumor infiltration and metastasis. Extensive studies have shown that ECM degradation can be enhanced by matrix metalloproteinase (MMP)-2, a zinc-dependent endopeptidase, thereby promoting tumor invasion and metastasis. Tissue factor pathway inhibitor (TFPI)-2 is a novel serine proteinase inhibitor which can inhibit the activity and expression of various proteases, including MMP-2. Therefore, TFPI-2 is considered a protector that prevents components of the ECM from degrading, thereby combating the infiltration and migration of tumor cells. A few studies have shown that there exists an opposite tendency in expression level of TFPI-2 and MMP-2 and that the anti-invasive properties of TFPI-2 are closely linked to MMP-2 inhibition.Aberrant expression of MMP-2 and TFPI-2 not only correlate with tumorigenesis, but also with tumor invasion, metastasis and angiogenesis. High expression of MMP-2, and low expression of TFPI-2 in pancreatic carcinoma has been previously elucidated. However, the association and clinical values of MMP-2 and TFPI-2 expression in pancreatic carcinoma remain unclear. In this study, in order to determine the levels of MMP-2 and TFPI-2 expression in tumor and paracarcinoma tissues, and analyze their relationships with tumor angiogenesis, clinicopathologic features, and prognosis in pancreatic carcinoma, immunostaining of MMP-2, TFPI-2, vascular endothelial growth factor (VEGF) and CD31 were then performed; and the correlations of MMP-2 and TFPI-2 staining with VEGF, microvessel density (MVD), clinicopathologic features, early postoperative recurrence, disease-free survival (DFS), and overall survival (OS) were therefore evaluated.ObjectiveThis work aimed to investigate the differential expression of MMP-2 and TFPI-2, and analyse their relationship with tumor angiogenesis, clinicopathologic data, early postoperative recurrence and survival time in pancreatic carcinoma.Methods(1) Immunohistochemistry was used to evaluate MMP-2 and TFPI-2 expression in tumor tissues and corresponding non-tumor tissues from 126 patients with pancreatic carcinoma. The correlation of MMP-2 and TFPI-2 expression in tumor tissues were analyzed.(2) Expression of VEGF and CD31 in tumor tissues was also assayed by immunostaining. The correlations of MMP-2 and TFPI-2 with VEGF, and MVD were analyzed.(3) The relationships of MMP-2 and TFPI-2 expression with clinicopathologic features were explored.(4) The relationships of MMP-2 and TFPI-2 with early postoperative recurrence, DFS, and OS of the patients were analyzed.Results(1) The results showed that MMP-2 expression was significantly increased (P =0.019) and TFPI-2 expression was significantly decreased (P<0.001) in pancreatic carcinoma tissues compared with paracarcinomatous tissues. Spearman’s rank correlation test showed a negative correlation between MMP-2 and TFPI-2 expression (r=-0.447, P<0.001).(2) Spearman’s rank correlation test showed that MMP-2 expression was positively correlated with VEGF (r=0.594, P<0.001) and MVD (r=0.432, P 0.001) in carcinoma tissues. Conversely, TFPI-2 expression was negatively correlated with VEGF (r=-0.654, P<0.001) and MVD (r=-0.360, P<0.001) in carcinoma tissues.(3) Increased MMP-2 expression and reduced TFPI-2 expression are significantly linked to aggressive clinicopathological characteristics including higher preoperative serum CA19-9 levels, poor tumor differentiation, lymph node metastasis (LNM), perineural invasion (PNI) and advanced tumor stage (P <0.001), and early postoperative recurrence (P<0.001). However, there was no significant association between expression of MMP-2 and TFPI-2 and other clinicopathological parametres including age, gender, tumor size, tumor location (P>0.05).(4) Multivariate logistic regression analysis showed that up-regulated MMP-2 was an independent risk factor for early postoperative recurrence of pancreatic carcinoma (hazard ratio [HR]=6.258; 95% confidence interval [CI] 1.478-26.503; P=0.013). However, up-regulated TFPI-2 was an independent protective factor against early postoperative recurrence (HR=0.137; 95% CI 0.040-0.467; P =0.001). Receiver operating characteristic curve (ROC) analysis showed that the combination of MMP-2 and TFPI-2 was a reliable predictive model for early postoperative recurrence of pancreatic carcinoma (area under the curve [AUC] =0.890; 95% CI 0.816-0.963; P<0.001).(5) Kaplan-Meier survival analysis and the log-rank test showed that high MMP-2 expression was significantly correlated with decreased DFS (P<0.001) and OS (P <0.001), while high TFPI-2 expression was significantly associated with increased DFS (P<0.001) and OS (P<0.001) in patients with pancreatic carcinoma. Cox proportional hazards regression model showed that poor tumor differentiation (HR=0.515; 95% CI 0.304-0.871; P=0.013), PNI (HR=2.141; 95% CI 1.296-3.538; P=0.003) and advanced tumor stage (HR=3.727; 95% CI 2.049-6.777; P<0.001) were independent predictors for reduced DFS; and poor tumor differentiation (HR=0.174; 95%CI 0.081-0.376; P<0.001), PNI (HR =1.704; 95% CI 1.020-2.845; P=0.042), and low TFPI-2 expression (HR=0.342; 95% CI 0.146-0.798; P=0.013) were independent prognostic factors for reduced OS.ConclusionIn conclusion, our findings suggest that the differential expression of MMP-2 and TFPI-2 have a negative correlation in pancreatic carcinoma tissues. Increased MMP-2 expression and reduced TFPI-2 expression are closely linked to tumor angiogenesis, aggressive clinicopathological characteristics, early postoperative recurrence, decreased DFS, and decreased OS in pancreatic carcinoma. Immunohistochemical assay of MMP-2 and TFPI-2 may be useful for predicting unfavourable prognosis of pancreatic carcinoma after surgery. |
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