Tissue factor and cell signalling in cancer progression and thrombosis

Abstract

The close link between coagulation activation and clinical cancer is well established and recent progress has defined underlying molecular pathways by which tumour cells interact with the haemostatic system to promote cancer progression. Tumour type-specific oncogenic transformations cause constitutive and hypoxia-dependent upregulation of tissue factor (TF) in cancer cells, but TF expressed by vascular, stromal and inflammatory cells also contributes to the procoagulant character of the tumour microenvironment. A growing body of genetic and pharmacological evidence implicates signalling by protease activated receptors (PARs) and specifically by tumour cell-expressed TF-VIIa-PAR2 in the induction of an array of proangiogenic and immune modulating cytokines, chemokines and growth factors. Specific inhibition of this pathway results in attenuated tumour growth and angiogenesis. PARs are increasingly recognised as targets for proteases outside the coagulation system and emerging evidence indicates that alternative protease signalling pathways synergise with the coagulation system to promote tumour growth, angiogenesis and metastasis. The elucidation of new therapeutic targets in tumour-promoting protease signalling pathways requires new diagnostic approaches to identify patients that will benefit from tailored therapy targeting procoagulant or signalling aspects of the TF pathway.

Fig. 1. Model of PAR2 recognition by VIIa

The molecular docking model of PAR2 interaction with the VIIa protease domain highlights the key interaction of the PAR2 P2 residues with T⁹⁹ and the PAR2 P2′ residues with the pocket formed by Q⁴⁰, Q¹⁴³, and T¹⁵¹; illustration courtesy of H. Østergaard.

Fig. 2. TF Signalling Complexes

Schematic overview of the co-receptors involved in TF binary and ternary complex signalling. TF-specific inhibitors targeting the binary or ternary complex are listed.

Fig. 3

Tumour cell TF-VIIa-PAR2 signalling promotes angiogenesis dependent on G-protein-coupled receptor signalling and the TF cytoplasmic domain.