Alternatively spliced tissue factor induces angiogenesis through integrin ligation

Abstract

The initiator of coagulation, full-length tissue factor (flTF), in complex with factor VIIa, influences angiogenesis through PAR-2. Recently, an alternatively spliced variant of TF (asTF) was discovered, in which part of the TF extracellular domain, the transmembrane, and cytoplasmic domains are replaced by a unique C terminus. Subcutaneous tumors produced by asTF-secreting cells revealed increased angiogenesis, but it remained unclear if and how angiogenesis is regulated by asTF. Here, we show that asTF enhances angiogenesis in matrigel plugs in mice, whereas a soluble form of flTF only modestly enhances angiogenesis. asTF dose-dependently upregulates angiogenesis ex vivo independent of either PAR-2 or VIIa. Rather, asTF was found to ligate integrins, resulting in downstream signaling. asTF-␣V␤3 integrin interaction induces endothelial cell migration, whereas asTFdependent formation of capillaries in vitro is dependent on ␣6␤1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to ␤1 and ␤3 integrin blockade and a TF-antibody that disrupts asTFintegrin interaction. We conclude that asTF, unlike flTF, does not affect angiogenesis via PAR-dependent pathways but relies on integrin ligation. These findings indicate that asTF may serve as a target to prevent pathological angiogenesis.cancer ͉ coagulation ͉ endothelial cells ͉ integrins

Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

“…Strikingly, murine ECs do not appear to engage β1 integrins while adhering to masTF (Figure 2), yet both β1 and β3 integrins are required for masTFelicited angiogenesis, analogously to the hasTF ( Figure 4) (21). It should be noted that β3-deficient mice exhibit a pathological enhancement of angio genesis rather than inhibition of vessel growth (35); however, aberrations triggered by global β3 deficiency may not be reflective of the effects elicited by soluble β3 ligands (for example, masTF/hasTF) in select tissue subcompartments (for example, the vasculature).…”

“…We recently reported that hasTF induces angiogenesis and promotes monocyte-endothelial interactions via integrin ligation, without engaging protease activity (21,22). Thus, hasTF may be of interest in the field of anticancer therapies targeting neovascularization.…”

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

“…In contrast to flTF, asTF was demonstrated to mediate cell signaling independently of PAR-2 (10,21,24 ). In 2009, van den Berg and colleagues found that asTF directly binds to ␤3 and ␤1 integrins.…”

Crosstalk between cancer and haemostasis

“…Furthermore, the TF cytoplasmic domain may be directly involved in the expression of vascular endothelial growth factor (VEGF) in tumour cells (53), and TF has been shown to regulate cell migration via interaction with integrin alpha3beta1 and actin-binding protein 280 (54 ,55). In this regard it is noteworthy that alternatively spliced TF is also capable of inducing angiogenesis through ligation of various integrins, conferring additional complexity to the issue (56).…”