Pathological activation of coagulation contributes to the high incidence of venous
thromboembolism in different types of cancer, in particular, gastrointestinal tumors.
Besides this, single coagulation factors are able to promote cancer development by
direct effects on tumor cell signaling mechanisms. One of the best described coagulation
components implicated in tumor growth and metastasis is tissue factor (TF), which
can be expressed by various tumor cells. TF in complex with factor VIIa (FVIIa) initiates
the extrinsic arm of fibrin formation and, independently, activates cell signaling
via protease activated receptors (PARs).[1] The thoroughly conducted study by Featherby et al[2] adds a new layer to the coagulation–cancer cell connection by highlighting the role
of FVIIa both for the release of TF+ microvesicles (MVs) and for tumor cell proliferation, as well as the inhibition of
these effects by distinct direct oral anticoagulants. MVs are a species of extracellular
vesicles that might support tumor progression by various mechanisms such as, for example,
through delivery of their RNA cargo into the immune cell cytosol via the scavenger
receptor CD36.[3] PAR2 activation by FVIIa is suggested to be responsible for the enhancement of MV
secretion and tumor cell proliferation.[2] The direct FXa inhibitor apixaban, but not the FXa inhibitor rivaroxaban, decreases
the proteolytic activity of FVIIa and, consequently, the signaling function of PAR2
in cell proliferation. Based on calculations of the binding energies for the apixaban–FVIIa
interaction, the authors suggest that the affinity of apixaban for FVIIa is in a comparable
range as its affinity for FXa. By inhibiting cancer cell proliferation, the release
of distinct extracellular vesicles, and coagulation activation per se, some FXa inhibitors
could potentially target synchronously several different mechanisms of tumor progression.
Such conclusions will require confirmation from additional work, especially from in
vivo experiments.
