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Background/aim: Clotting factors promote cancer development. We investigated if coagulation proteins promote proliferation and migration in colorectal cancer (CRC) cell lines and whether their direct inhibitors can attenuate these effects., Materials and Methods: DLD-1 and SW620 cells were treated with tissue factor (0, 50, 100 and 500 pg/mL ± 10 μg/mL 10H10 [anti-tissue factor antibody]), thrombin (0.0, 0.1, 1.0 and 10.0 U/mL ± 0.5 μM dabigatran [thrombin inhibitor]) and Factor Xa, FXa (0.0, 0.1, 1.0 and 10.0 U/mL ± 100 ng/mL rivaroxaban [FXa inhibitor]) and their effects on proliferation and migration were quantified using the PrestoBlue® and transwell migration assays, respectively., Results: Thrombin increased proliferation from 48 h treatment compared to its control (48 h 6.57 ± 1.36 u vs. 2.42 ± 0.13 u, p = 0.001, 72 h 9.50 ± 1.54 u vs. 4.50 ± 0.47 u, p = 0.004 and 96 h 10.77 ± 1.72 u vs. 5.57 ± 0.25 u, p = 0.008). This increase in proliferation was attenuated by dabigatran at 72 h (2.23 ± 0.16 u vs. 3.26 ± 0.43 u, p = 0.04). Tissue factor (0 pg/mL 20.7 ± 1.6 cells/view vs. 50 pg/mL 32.4 ± 1.9 cells/view, p = 0.0002), FXa (0.0 U/mL 8.9 ± 1.1 cells/view vs. 10.0 U/mL 17.7 ± 1.7 cells/view, p < 0.0001) and thrombin (0.0 U/mL 8.9 ± 1.3 cells/view vs. 10.0 U/mL 20.2 ± 2.0 cells/view, p < 0.0001) all increased migration compared to their controls. However, their direct inhibitors did not attenuate these increases., Conclusion: Thrombin, FXa and TF all increase migration in CRC in vitro. Thrombin induced increase in proliferation is abrogated by dabigatran. Dabigatran may have potential as an anti-cancer therapy in CRC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Tissue factor (TF) expression increases cancer stem cell (CSC) activity in breast and lung cancer. There are ongoing studies focused on targeting CSCs via anti-TF treatment, for breast and lung cancer therapy. Herein, the aim was to determine whether targeting TF could have an anti-CSC therapeutic role in colorectal cancer (CRC)., Materials and Methods: Evaluation of colonosphere-forming efficiency (CFE) and aldehyde dehydrogenase (ALDH) expression level was used to quantify CSC activity in two CRC cell lines, after TF knockdown (TFKD) or TF over-expression (TFOE)., Results: TFKD resulted in increased levels of ALDH in SW620 (1.31±0.04-fold, p<0.001) and DLD-1 (1.63±0.14-fold, p=0.04) cells. CFE was increased in SW620 (1.21±0.23% vs. 2.03±0.29%, p=0.01) and DLD-1 (0.41±0.12% vs. 0.68±0.9%, p=0.01) cells. Conversely, TFOE decreased ALDH expression (0.72±0.04-fold, p=0.001) and CFE (0.33±0.05% vs. 0.66±0.14%, p=0.006) in DLD-1, but had no impact on SW620 cells., Conclusion: In the examined CRC cell lines, TF expression was inversely related to CSC activity suggesting that anti-TF therapies may not have a role in CRC treatment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Significance: Colorectal cancer (CRC), results in a hypercoagulable state which manifests clinically as venous thromboembolism (VTE), often presenting as a deep vein thrombosis (DVT) or pulmonary embolism (PE). The consequences of VTE in CRC can be devastating, resulting in long-term morbidity and are a frequent cause of death, even amongst those who would have otherwise had a favourable cancer prognosis. The incidence of VTE in all cancers is increasing, whilst the exact incidence of VTE in CRC is likely to be underestimated. All cancer treatments increase the risk of VTE in an already at risk population., Critical Issues: CRC-associated VTE is a challenging entity to manage with recurrences occurring more frequently in cancer patients, despite anticoagulation. Anticoagulation, whether treatment or prophylactic, increases the risk of bleeding, especially in patients with cancer. Although strong evidence underpins the initial management of cancer-associated VTE, there is uncertainty with regard optimum treatment duration. For VTE prevention, extended (28 days), pharmacological thromboprophylaxis post CRC surgery is internationally recommended. Pharmacological thromboprophylaxis is not routinely recommended for nonhospitalised patients receiving chemotherapy., Future Directions: There is growing evidence of a symbiotic relationship between cancer biology and the clotting system. Tissue factor (TF), the initiator of the clotting pathway, promotes cancer via clotting dependent and independent mechanisms. Clotting pathway factors, including TF, may have utility as biomarkers in CRC, for assessment of VTE risk in addition to cancer prognosis. The clotting system may also be a target for potential anti-cancer therapies, either via existing anticoagulants or experimental direct TF inhibitors.