Implication of Hepsin from primary tumor in the prognosis of colorectal cancer patients

Abstract

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.

Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

“…Instead, hepsin activity is regulated downstream via a Ras pathwaydependent mechanism [7]. However, in our recently published study, we found no association between Ras mutation and hepsin levels [13].…”

“…In fact, thromboembolic disease is often associated with metastasis [46]. Hepsin overexpression of our cell line clearly increased procoagulant phenotype as we observed in localized CRC patients [13]. These observations led us to hypothesize that some TTSPs, including hepsin, contribute to hypercoagulability in vivo by generating thrombin in the phase boundary of the tumor invasion and migration front, together with other mediators [49,50].…”

“…Information about the role of hepsin in CRC is exceedingly scant. Recently, we have identified hepsin as a prognostic marker of metastasis and thrombosis in patients with localized tumor [13]. This led us to explore possible hepsin-mediated mechanisms that might link to CRC tumorigenesis and thrombotic risk, as well as to search for drugs that target this TTSP.…”

“…The fact that hepsin is differentially more expressed in the plasma of metastatic patients could be due to its release by the cells from the metastasis sites and not from the primary tumor, where the role of hepsin would no longer be as relevant. In fact, hepsin levels in the primary tumor are lower the greater the number of metastases is [13].…”

“…Consequently, the results should be interpreted as hypothesis generators, to be reviewed later. In addition, there is no correlation between the findings found in plasma and biopsies of patients with CRC [13], so more studies are needed to determine the potential of hepsin as a biomarker and as a therapeutic target. Second, although the study sheds light on the status of two key pathways in CRC (Erk1/2 and JAK2/STAT3 signaling pathways), the causal order is unclear in this case.…”