Abstract Number: PB2160
Meeting: ISTH 2020 Congress
Theme: Venous Thromboembolism and Cardioembolism » Cancer Associated Thrombosis
Background: Colorectal cancer (CRC) is associated with a high risk of thrombosis. Besides its key function in hemostasis, the activated coagulation factor-X (FXa) directly stimulates cellular effects via activation of the G-protein-coupled protease-activated receptors PAR1 and PAR2.
Aims: The aim of the current study was to characterize direct effects and underlying signaling mechanisms of FXa in CRC cell migration and proliferation.
Methods: Human (HCT116, CaCo2) and murine (MC38) CRC cell lines were stimulated with a range of physiological FXa concentrations. Selective agonist peptides for PAR1 and PAR2 were used to characterize their functions. Cell migration was determined in wound scratch and Boyden chamber migration assays; proliferation by BrdU (bromdesoxyuridin) incorporation and cell counting. Signaling pathways were analyzed by Western blotting.
Results: Stimulation of murine MC38 cells with FXa (0.1-30 nM) significantly increased directed and undirected cell migration within 24 hours up to 2-fold. In comparison, proliferation of MC38 cells was at a high basal level already and was not further stimulated by FXa. Human CaCo2 cells exhibited an attenuated migration response, while proliferation was significantly increased after stimulation with FXa. In HCT116 cells, FXa significantly enhanced both cell migration and proliferation. These effects were mimicked by peptide-stimulated activation of PAR2 but not PAR1. In addition, incubation with FXa significantly increased phosphorylation of p44/42, p38 and AKT in MC38 and HCT116 cells in a time-dependent manner. The EGF (epidermal growth factor) receptor inhibitor Erlotinib markedly attenuated FX-induced cell migration in CRC cells, indicating transactivation of the EGF receptors as an underlying mechanism.
Conclusions: FXa directly stimulates proliferation and migration of various CRC cell lines in vitro. This involves p44/42, p38 and AKT signaling pathways and may involve transactivation of the EGF receptor. Use of suitably FXa inhibitors to reduce the thromboembolic risk in CRC patients may simultaneously attenuate tumor progression.
To cite this abstract in AMA style:
Meyer U, Polster S, Moritz E, Rauch BH. The Activated Coagulation Factor X (FXa) Directly Stimulates Colorectal Cancer Cell Migration and Proliferation – Characterizing the Underlying Molecular Mechanisms [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-activated-coagulation-factor-x-fxa-directly-stimulates-colorectal-cancer-cell-migration-and-proliferation-characterizing-the-underlying-molecular-mechanisms/. Accessed March 22, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-activated-coagulation-factor-x-fxa-directly-stimulates-colorectal-cancer-cell-migration-and-proliferation-characterizing-the-underlying-molecular-mechanisms/