Tumor-expressed Factor VII associates with survival and regulates tumor progression in breast cancer.

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.