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Hepsin is a type II transmembrane serine protease whose deregulation promotes tumor invasion by proteolysis of the pericellular components. In colorectal cancer, the implication of hepsin is unknown. Consequently, we aimed to study the correlations between hepsin expression and different clinical-histopathological variables in 169 patients with localized colorectal cancer and 118 with metastases. Tissue microarrays were produced from samples at diagnosis of primary tumors and stained with an anti-hepsin antibody. Hepsin expression was correlated with clinical-histopathological variables by using the chi-square and Kruskal–Wallis tests, Kaplan–Meier and Aalen–Johansen estimators, and Cox and Fine and Gray multivariate models. In localized cancer patients, high-intensity hepsin staining was associated with reduced 5-year disease-free survival (p-value = 0.16). Medium and high intensity of hepsin expression versus low expression was associated with an increased risk of metastatic relapse (hazard ratio 2.83, p-value = 0.035 and hazard ratio 3.30, p-value = 0.012, respectively), being a better prognostic factor than classic histological variables. Additionally, in patients with localized tumor, 5-year thrombosis cumulative incidence increased with the increment of hepsin expression (p-value = 0.038). Medium and high intensities of hepsin with respect to low intensity were associated with an increase in thrombotic risk (hazard ratio 7.71, p-value = 0.043 and hazard ratio 9.02, p-value = 0.028, respectively). This relationship was independent of previous tumor relapse (p-value = 0.036). Among metastatic patients, low hepsin expression was associated with a low degree of tumor differentiation (p-value < 0.001) and with major metastatic dissemination (p-value = 0.023). Hepsin is a potential thrombotic and metastatic biomarker in patients with localized colorectal cancer. In metastatic patients, hepsin behaves in a paradoxical way with respect to differentiation and invasion processes.

BackgroundHepsin is a type II transmembrane serine protease whose functions include degradation of the extracellular matrix and activation of factor VII. In many tumors, hepsin dysregulation leads to tumor invasion by proteolysis of pericellular components. Colorectal cancer is a tumor with high thrombotic and metastatic risk, but the role of hepsin is unknown.ObjectivesTo study the correlations between hepsin expression in the primary tumor and different clinical-histopathological variables in patients with localized and metastatic colorectal cancer.MethodsA cohort of 287 patients, 169 with localized colorectal cancer and 118 with metastases at diagnosis, was recruited. Tissue microarrays were made from samples at diagnosis of primary tumors and stained with an anti-hepsin antibody. Hepsin levels were determined and the association with clinical-histopathological variables was evaluated using the chi-square and Kruskal-Wallis tests. Time-to-event results and cumulative incidence functions were calculated using Kaplan-Meier and Aalen-Johansen estimators, in combination with Cox and Fine&Gray multivariate models.ResultsIn patients with localized colorectal cancer, high intensity hepsin staining was associated with reduced 5-year disease-free survival (p-value = 0.16). In this context, according to multivariable Cox regression, medium and high intensity of hepsin expression versus low intensity was associated with an increased risk of metastatic relapse (hazard ratio 2.83, p-value=0.035, and hazard ratio 3.30, p-value=0.012, respectively), being a more accurate prognostic factor than classic histological variables. Also, in patients with localized colorectal cancer, the cumulative incidence of thrombosis at 5 years increased significantly with higher hepsin levels (p-value = 0.038). According to the multivariate Fine&Gray regression, the medium and high intensity of hepsin with respect to the low intensity, was associated with an increase in thrombotic risk (hazard ratio 7.71, p-value=0.043 and hazard ratio 9.02, p-value=0.028, respectively). This relationship between hepsin and thrombosis was independent of previous tumor relapse (p-value = 0.036). In patients with metastatic colorectal cancer, low intensity of hepsin was associated with a low degree of tumor differentiation (p-value <0.001) and spread to more than one metastatic site (p-value = 0.023).ConclusionHepsin is a potential biomarker of thrombosis and metastasis in patients with localized colorectal cancer. Validation in a larger series and clarification of the underlying mechanism may be helpful in evaluating these patients. In metastatic patients, Hepsin behaves in a paradoxical way with respect to differentiation and invasion processes.

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