Tissue factor isoforms and cancer (Yascha van den Berg)

Tissue factor isoforms and cancer

(Yascha van den Berg)

Proefschrift te verkrijging van de graad van Doctor aan de Universiteit Leiden op gezag van Rector Magnificus prof. Mr. C.J.JK.M. Stolker, volgens besluit van het College voor Promoties te verdedigen op dinsdag 8 oktober 2013, klokke 15:00 uur door Yascha Wilfred van den Berg, geboren te Leidschendam in 1982

Full-length tissue factor (flTF) is a 47 kDa transmembrane glycoprotein that is primarily responsible for activation of the coagulation cascade along the extrinsic pathway. Upon vessel damage, subendothelial expressed flTF forms a complex with circulating factor VII/VIIa (FVII/FVIIa) that can subsequently activate factor X (FX) and thrombin, resulting in localized formation of fibrin required for hemostasis. flTF expression is classically thought to be limited to subendothelial tissues in order to serve as a hemostatic envelope surrounding the vasculature1;2. However, in specific conditions, circulating monocytes, endothelium and circulating microparticles can bear membrane-bound flTF as well3;4 . Besides its important role in initiating the coagulation cascade, flTF is involved in numerous physiological and pathological processes like angiogenesis and inflammation. flTF expression on endothelium and circulating microparticles underlies thrombotic complications in cancer and sepsis due to flTF’s coagulant activity, but non-hemostatic properties of flTF also influence tumor biology and inflammatory processes.

The study of flTF-/- mice showed that flTF is indispensable for embryonic pericyte function and therefore to be critical for embryonic angiogenesis5 . In adults, flTF’s role in angiogenesis comprises wound healing, neovascularization and tumor angiogenesis. The last years, extensive research provided insight in how flTF triggers several cellular signaling pathways involved in cell growth, cell migration and cell survival6-12. Examination of mice that express TF lacking the cytoplasmic domain indicated that this domain is not required for and may even inhibit angiogenesis. These results support the notion that flTF may only affect angiogenesis indirectly via downstream coagulation factors13;14. In subsequent studies, however, direct activation of the membrane bound G-protein coupled protease activated receptor 2 (PAR2) by either the flTF/FVIIa/fXa-complex or the flTF/FVIIa-complex was reported15;16. These direct activation routes obviate the need for downstream coagulation factors and the formation or breakage of the disulfide bond between Cys186 and Cys209 has been claimed to switch between either signaling or pro-coagulant activity of flTF. It should be noted though that there remains controversy regarding the role of disulfide switching and this remains an area of ongoing research12;17-19 . Binding and activation of integrins is a second FVII/FVIIa-independent and non-hemostatic property of flTF. Integrins are heterodimeric complexes consisting of an α and β subunit that play a critical role in cellular mechanisms involved in angiogenesis, wound healing and cancer biology20. flTF can directly bind to β1 integrins and this binding results in activation of integrins, but also in an active state of the flTF:FVIIa:PAR2 complex, thus allowing for flTF signaling21 .

Paperback, 193 pag.

Uitg, Universiteit Leiden, 2013

ISBN: geen

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