Tumor cell–associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell–dependent and–independent mechanisms

Abstract

IntroductionTissue factor (TF) is the membrane-associated glycoprotein receptor for coagulation factors VIIa and X that serves as the primary physiologic initiator of blood coagulation. In addition to supporting proteolytic events that ultimately lead to local thrombin generation, TF is also proposed to directly contribute to intracellular signaling events through the TF cytoplasmic domain and TF/fVIIa/fXamediated activation of PAR-1 and PAR-2. 1-4 A significant body of evidence has accumulated linking tumor cell-associated procoagulant function to cancer biology. Multiple clinical studies have shown a correlation between TF expression by tumor cells and advanced disease stage and poor outcome. [5][6][7][8][9] Furthermore, experimental data generated using animal models of tumor metastasis strongly favor the view that TF expression by malignant cells supports metastatic success. [10][11][12][13][14][15] Similarly, thrombin-mediated proteolysis, 16-21 fibrin(ogen), 22,23 and PAR-mediated platelet activation 24 also appear to be significant determinants of metastatic potential. Both platelets and fibrinogen were shown to support metastatic potential by limiting the capacity of natural killer (NK) cells to clear newly established micrometastatic foci. 25,26 However, hemostatic factors are likely to influence tumor dissemination through multiple mechanisms and the precise pathways coupling TF to malignancy remain to be defined.The tandem importance of tumor cell-associated TF and circulating coagulation system components in malignancy is consistent with the hypothesis that TF supports metastasis by providing cancer cells a means of directing proteolytic events leading to local thrombin generation and the formation of tumor cell-associated microthrombi. However, an intriguing alternate possibility is that TF supports tumor cell dissemination by mechanism(s) uncoupled from "traditional" thrombin generation and subsequent thrombus formation. In this regard, significant attention has focused on potential intracellular signaling events coupled to the cytoplasmic portion of TF. This interest was driven in part by early studies indicating that tumor cells expressing a mutant form of TF lacking the cytoplasmic domain were far less metastatic than tumor cells expressing full-length TF. 11,12,14 However, interpretation of these early studies was made more complex by the use of nonmurine tumor lines in xenograft assays in mice, the use of tumor cells expressing human TF or human TF derivatives in a setting where all other factors were of murine origin, and the requisite use of immunocompromised mice. Nevertheless, many studies have provided provocative evidence for an important linkage between TF-mediated signaling events and several key cellular processes capable of influencing metastasis, including cytoskeletal organization, 27 cell adhesion/migration, 28-30 apoptosis, 31,32 and angiogenesis. 33,34 An important role for the TF cytoplasmic domain in cellular signaling is also supported by more recent studies of transgenic mic...

Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease

“…Tissue factor is highly expressed in metastatic, but not in non-metastatic breast carcinoma cells (Bluff et al, 2006), and may contribute to the metastatic process directly through the TF-FVIIa complex and/or through downstream generation of active coagulation factors (Booden et al, 2004;Palumbo et al, 2007). Furthermore, TF-FVIIa signalling via PAR-2 has been shown to stimulate breast cancer cell migration (Jiang et al, 2004;Morris et al, 2006), and a humanised anti-TF monoclonal antibody (CNTO 859) inhibited experimental in vivo lung metastasis from invasive breast cancer cells by more than 99%, indicating a role for TF in breast cancer cell metastasis (Ngo et al, 2007).…”

Microenvironmental regulation of metastasis

“…Tumour cells express tissue factor, the receptor for coagulation factors VIIa and X, which serves as the main initiator of coagulation, and has an important role in supporting thrombin-mediated proteolysis and the formation of tumour cell-associated microthrombi 74,75 . The platelet aggregate increases cancer cell survival through protection from NK cell-mediated lysis 76,77 , but also through an independent signalling mechanism coupled to circulating prothrombin 77 . The fibrin clots may also reduce shear forces that can destroy individual circulating cancer cells, and facilitate the slowing, arrest and adhesion of cancer cells, thus increasing their ability to extravasate at a secondary site.…”

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

“…Notably, pharmacological and genetic strategies targeting TF, FVIIa, thrombin, platelets and other coagulation mechanisms led to anti-tumor and anti-metastatic effects [61,[92][93][94][95][96], which are often comparable to other 'main stream' targeted agents [87,93].…”