Alternatively spliced tissue factor

Summary

Full-length tissue factor (flTF) initiates coagulation, but also exerts non-hemostatic functions such as inflammation and angiogenesis through protease activated receptors (PARs). In 2003 a soluble variant of flTF was described which results from alternative splicing. Since its discovery the role of alternatively spliced tissue factor (asTF) in coagulation has been debated. asTF may have pro-coagulant properties but due to structural differences when compared to flTF, asTF coagulant function may be relatively low. Nevertheless, similar to flTF, asTF appears to have non-hemostatic properties; asTF expression in tumors correlates with increased tumor size, vessel number and poor survival in some cancer types, and drives tumor growth in animal models. Interestingly, unlike flTF, asTF does not promote angiogenesis through activating PARs but rather via integrin ligation. flTF is a critical determinant in cardiovascular disease but little is known about asTF in cardiovascular disease. asTF is produced by monocytes and macrophages, thus macrophage-derived asTF may contribute to atherosclerotic disease. In conclusion, unraveling asTF’s non-hemostatic properties may generate new insights in the pathophysiology and diagnostics of cancer and cardiovascular disease.

Zusammenfassung

Der flTF (full length tissue factor) initiiert die Gerinnung, verfügt aber durch die Protease-aktivierten Rezeptoren (PARs) auch über andere Funktionen, wie Inflammation und Angiogenese. Im Jahr 2003 wurde eine lösliche Variante des flTF beschrieben, die durch ein alternatives Splicing entsteht. Seit seiner Entdeckung wird über die Rolle des alternativ gespleißten Tissue-Faktors (asTF) bei der Gerinnung diskutiert. Der asTF könnte gerinnungsfördernde Eigenschaften besitzen, aufgrund struktureller Unterschiede im Vergleich zu flTF ist die Gerinnungsfunktion bei asTF jedoch möglicherweise relativ gering. Allerdings scheint asTF, ähnlich wie flTF, nicht hämostatischen Eigenschaften zu besitzen; die Expression von asTF in Tumoren korreliert positiv mit der Tumorgröße, der Anzahl der Gefäße und einem schlechteren Überleben bei bestimmten Tumorarten und verstärkt in Tiermodellen das Tumorwachstum. Interessanterweise fördert asTF im Gegensatz zu flTF die Angiogenese nicht über die Aktivierung der PARs, sondern vielmehr über die Ligation von Integrinen. Von zentraler Bedeutung ist flTF bei kardiovaskulären Erkrankungen, man weiß jedoch wenig über die Rolle von asTF bei diesen Erkrankungen. asTF wird in Monozyten und Makrophagen gebildet, daher könnte asTF mit makrophagealem Ursprung zu arteriosklerotischen Erkrankungen beitragen. Abschließend kann man sagen, dass die Erforschung der nicht-hämostatischen Eigenschaften des asTF neue Einblicke in die Pathophysiologie und Diagnostik von Krebs und kardiovaskulären Erkrankungen schaffen könnte.

Keywords

Angiogenesis - cancer - cardiovascular disease - integrins

Schlüsselwörter

Angiogenese - Krebs - kardiovaskuläre Erkrankung - Integrine

• References

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