Modulation of the tissue Factor pathway by Syndecan-1 in triple negative breast cancer

Breast cancer is one of the most common causes of cancer death in women worldwide. Many cancer patients show a hypercoagulable status leading up to frequent severe complications, such as thromboembolism and haemorrhage. Furthermore, the risk of tumour-associated hypercoagulability is associated with the effects of chemotherapy and radiotherapy on the coagulation cascade. Tissue factor (TF) is an important mediator of coagulation and a potent stimulator of the extrinsic coagulation cascade. It also enhances cell proliferation and migration. Angiogenesis and haemostasis are two of the most reliable host responses linked with cancer. Poor prognosis is associated to dysregulation of the cell surface proteoglycan and signaling co-receptor Syndecan-1 (Sdc-1). We silenced Sdc-1 in TNBC cell lines utilizing a 3D human umbilical vein endothelial cell (HUVEC) co-culture system to examine the role of Sdc-1 in angiogenesis and the modulation of the tissue factor pathway. Furthermore, we used multiple molecular and functional experiments to examine the potential link between Sdc-1 knockdown and TF pathway inhibitor (TFPI). Sdc-1 siRNA depletion reduced HUVEC tubule network formation in the cell lines. In the Sdc-1-silenced secretome, angiogenesis array indicated lower levels of VEGF-A and TF. Altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in cell lines was validated by qPCR. Sdc-1 knockdown resulted in lower secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) levels, while TFPI treatment inhibited angiogenesis. Our study demonstrates a novel link between TFPI and Sdc-1 in breast cancer cells, indicating their potentials as novel prognostic markers and therapeutic targets.

Publication History

Article published online:
21 June 2022