Tumor-expressed factor VII is associated with survival and regulates tumor progression in breast cancer

Abstract

Cancer enhances the risk of venous thromboembolism, but conversely a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful, for unknown reasons. In normal physiology, complex formation between the subundothelial-expressed Tissue Factor (TF) and the blood-borne liver-derived FVII results in induction of the extrinsic coagulation cascade and intracellular signaling via protease activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here we report that increased levels of FVII are also observed in breast cancer specimens and associate with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition, tumor cell invasion and expression of the pro-metastatic genes SNAI2 and SOX9. In vivo, tumor-expressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII induced pro-metastatic gene expression independent of TF, but required functional endothelial protein C receptor (EPCR), while recombinant FVIIa acting via the canonical TF:PAR2 pathway inhibited pro-metastatic gene expression. We propose here that tumor-expressed FVII and liver-derived FVII have opposing effects on EMT and metastasis.

Bioinformatics analysis reveals link between alternative complement cascade pathway and colorectal cancer liver metastasis

“…In this process, the interaction of substances involved in blood coagulation not only directly leads to the hypercoagulation state but also promotes the proliferation and in ltration of tumor cells by activating related pathways and provides a scaffold for tumor cells to adhere to and metastasize while helping them evade normal immune surveillance. Extrahepatic coagulation factor VII (FVII) produced by CRC cells can promote tumor invasion and metastasis by upregulating the expression of MMP [32] . Compared with the CRC dataset, ALB, FGG, SERPINC1, AHSG, APOA1, F2, AMBP, APOH, APOB, and KLF20A were the top 10 hub genes in the CRC liver metastasis dataset.…”