Tissue factor in hematological malignancies

It is now recognized that there is an increasing body of evidence supporting the link between the various components of the coagulation/fibrinolysis systems and angiogenic activity in cancer patients.¹ Platelets contains several positive and negative regulators of angiogenesis (Table 1). Tissue factor (TF), thrombin, fibrinogen, fibrin and plasminogen activator system, as well as platelets, are all able to promote angiogenesis. On the other hand, coagulation inhibitors, as well as proteolytically released domains of hemostatic proteins, are also known to act as angiogenesis inhibitors. Judah Folkman speculated that ‘during the first days of wound healing as nascent clot bridges and stabilizes the vessel defect, any initiation of angiogenesis directed by platelet-derived angiogenic stimulators, or by thrombin and fibrin, must be counteracted’.²

Table 1 Positive and negative regulators of angiogenesis carried by platelets

TF is a cell-associated receptor for coagulation factor VII/VIIa, an interaction known to activate the coagulation cascade. At the same time, TF is also known as a mediator of intracellular signaling events that can alter gene expression patterns and cell behavior. It has become clear that TF functions as a cytokine-like receptor and this notion was confirmed by the discovery of coagulation-independent actions of TF, including regulation of tumor growth, angiogenesis, as well as regulation of inflammation and sepsis.³

Both clotting-dependent and -independent mechanisms of TF-induced angiogenesis have been elucitated.⁴ Clotting-dependent induction of tumor angiogenesis is primarily mediated by TF-induced generation of thrombin and subsequent deposition of cross-linked fibrin. A cross-linked fibrin network provides a provisional proangiogenic matrix that facilitates blood vessel infiltration. Clotting-independent mechanisms of TF-induced tumor angiogenesis have also been described, mediated primarily by the cytoplasmatic tail of the TF receptor. Both aspects of TF activity are of possible relevance to tumor growth, metastasis and angiogenesis, including upregulation of vascular endothelial growth factor (VEGF). TF status is known to affect expression of other angiogenesis stimulators, such as fibroblast growth factor-4 (FGF-4) and interleukin-8 (IL-8), and inhibitors, such as thrombospondin-1 and -2 (TSP-1, TSP-2).⁵ TF upregulation is often observed on the surfaces of tumor-associated endothelial cells, inflammatory cells, and particularly on cancer cells themselves. In the last case, high TF levels may be associated with poor prognosis and parallel clinical and genetic tumor progression.

In the present issue of Leukemia, Lòpez-Pedrera et al.⁶ publish a review article focused on the current knowledge about the mechanisms by which TF promotes angiogenesis and invasiveness in hematological malignancies. The role of angiogenesis in the growth and survival of leukemias and other hematological malignancies has been rendered evident since 1994 in a series of demonstrations showing that the progression of several forms is clearly related to their degree of angiogenesis (Table 2).

Table 2 Historical review of angiogenesis involvement in hematological malignancies

Lymphomas and some other hematological malignancies, such as multiple myeloma and myeloproliferative disorders, described to be associated to the development of thrombotic events, have now been reported in relation to their association with aberrant TF expression. The incidence of severe complications, such as disseminated intravascular coagulation (DIC) in malignant lymphoma might involve elevated cytokine expression by lymphoma cells stimulating the expression of TF in blood cells or surrounding tissue. It has been described an increased expression of TF in patients with acute myeloid leukemia (AML), accounting for an increased risk of thrombohemorragic alterations. Both TF and VEGF, remarkably elevated and simultaneously expressed in blast AML cells, might determine an increase in tumor angiogenesis. These data have been confirmed by genomics and proteomics studies demonstrating that blast samples exhibited increased expression of both TF and VEGF. In multiple myeloma and myeloproliferative disorders the development of thrombotic events occurs, without any relationship with TF expression.

Upregulation of TF in cancer presents itself as an attractive therapeutic strategy.⁵ Direct targeting of TF in cancer should be considered in combination with other treatment modalities such as oncogene-directed therapies, antiangiogenic agents and anticancer chemotherapy. Moreover, anticoagulants, such as low molecular weight heparin, may act to prevent these complications both by interfering with TF-mediated activation of clotting and by directly downregulating angiogenesis. Thus, the use of retinoids for their differentiating activity in conjunction with specific antiangiogenic agents, such as anti-VEGF antibodies, would be useful in ameliorating both the angiogenesis and the coagulopathy seen in acute promyelocytic leukemia and other types of myeloid leukemias.