A possible role of plasmin-dependent activation of TGF-β in cancer-associated thrombosis: Implications for therapy.

Abstract

While the prevalence of cancer-associated thrombosis (CAT) is high in cancer patients, its molecular mechanisms have not been fully elucidated. Moreover, the risks of recurrent CAT events and mortality remain high in cancer patients despite the introduction of anticoagulant/antiplatelet therapy. Here, we discuss the possibility that increased plasmin activity driven by anticoagulant/antiplatelet treatment might be the major mechanism responsible for the activation of an excess of cancer-derived transforming growth factor-beta (TGF-β) originating from cancer cells and the tumour microenvironment. Hence, high coagulation and fibrinolysis rates in cancer patients may be linked to high rates of TGF-β activation, especially the excess of TGF-β derived from cancer cells. In turn, high TGF-β activation could contribute directly to maintaining high thrombotic risk and CAT recurrence in cancer patients since TGF-β signalling increases gene expression and secretion of the fibrinolysis inhibitor plasminogen activator inhibitor 1 (PAI1). Thus, TGF-β could directly contribute to the high number of deaths among patients with cancer experiencing CAT, despite anticoagulant/antiplatelet treatment. In a longer-term perspective, increased TGF-β activation, by supporting a pro-coagulant cancer microenvironment, might also accelerate cancer progression. This review aims to discuss the published evidence that might support the scenario described above, and to put forward the hypothesis that cancer patients experiencing CAT events would largely benefit from anti-TGF-β therapy.