Tissue Factor, Thrombin, and Cancer

178

122

The platelet paradigm in hemostasis and thrombosis involves an initiation step that depends on platelet membrane receptors binding to ligands on a damaged or inflamed vascular surface. Once bound to the surface, platelets provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin-rich network produced by coagulation factors. The platelet-specific receptor glycoprotein (GP) Ib-IX, is critical in this process and initiates the formation of a platelet-rich thrombus by tethering the platelet to a thrombogenic surface. A role for platelets beyond the hemostasis/thrombosis paradigm is emerging with significant platelet contributions in both tumorigenesis and inflammation. We have established congenic (N10) mouse colonies (C57BL/6J) with dysfunctional GP Ib-IX receptors in our laboratory that allow us an opportunity to examine the relevance of platelet GP Ib-IX in syngeneic mouse models of experimental metastasis. Our results demonstrate platelet GP Ib-IX contributes to experimental metastasis because a functional absence of GP Ib-IX correlates with a 15-fold reduction in the number of lung metastatic foci using B16F10.1 melanoma cells. The results demonstrate that the extracellular domain of the ␣-subunit of GP Ib is the structurally relevant component of the GP Ib-IX complex contributing to metastasis. Our results support the hypothesis that platelet GP Ib-IX functions that support normal hemostasis or pathologic thrombosis also contribute to tumor malignancy.adhesion ͉ tumor ͉ hemostasis ͉ knockout ͉ melanoma C irculating blood platelets have an inherent adhesive potential long recognized as essential for hemostasis and thrombosis. Beyond the platelet paradigm for blood clotting and thrombosis, it is becoming apparent that the platelet's adhesive potential influences pathological events outside its role in hemostasis. Indeed, emerging hypotheses suggest the platelet paradigm in hemostasis and thrombosis, an accumulation of platelets and the elaboration of a fibrin matrix, may provide a mechanism for circulating tumor cells to metastasize. Experimental proof that platelets effect tumor metastasis was provided in models where an experimental lowering of circulating platelet counts reduced metastasis (1-3).Evidence suggests that carcinoma cells entering the circulation interact with both platelets and leukocytes to form tumor cell aggregates (1, 4). Data have suggested one mechanism linking the platelet to metastasis is a platelet ''cloak'' surrounding the tumor cell and protecting the tumor cell from immune surveillance (5, 6). Tumorigenesis has been linked to several molecules essential for blood coagulation and normal platelet function. These include thrombin, tissue factor, platelet P-selectin, fibrinogen, and lysophosphatidic acid (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Together, these results suggest that platelets and their procoagulant activity support tumor metastasis, possibly by aiding tumor cells to lodge in the microvasculature and either extravasate...

Section: Discussionmentioning

confidence: 94%

Platelet glycoprotein Ibα supports experimental lung metastasis

Jain

Zuka

Liu

et al. 2007

178

122

“…It is conceivable that neutrophil activation and NET generation are important players in cancer-associated thrombosis but are not sufficient. Production of tissue factor by various tumors (38), for example, could further potentiate the prothrombotic state. In addition, our results indicate that a further activation of the innate immune system in a cancer patient could precipitate a thrombotic event and organ damage through NET-/ histone-induced injury.…”

Section: Discussionmentioning

confidence: 99%

Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

Demers

Krause

Schatzberg

et al. 2012

767

752

Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients.

“…Thrombin is important in the regulation of homeostasis and is associated with many types of cancer. Therefore, engineering probes that target thrombin and, moreover, whose function can be precisely regulated by photonic energy, can advance anticoagulation therapy for many diseases (24,25).Photoregulation of azobenzene conformation and DNA duplex structures using azobenzene is a well-known and studied phenomenon. We also believe that it is a key component to the functionalization of probes engineered to target thrombin.…”

mentioning

confidence: 99%

Using photons to manipulate enzyme inhibition by an azobenzene-modified nucleic acid probe

Kim

Phillips

Liu

et al. 2009

146

116

The ability to inhibit an enzyme in a specific tissue with high spatial resolution combined with a readily available antidote should find many biomedical applications. We have accomplished this by taking advantage of the cis-trans photoisomerization of azobenzene molecules. Specifically, we positioned azobenzene moieties within the DNA sequence complementary to a 15-base-long thrombin aptamer and then linked the azobenzene-modified cDNA to the aptamer by a polyethylene glycol (PEG) linker to make a unimolecular conjugate. During the photoisomerization of azobenzene by visible light, the inhibition of thrombin is disabled because the probe hybridizes with the cDNA in the trans-azobenzene conformation so that the aptamer cannot bind its target thrombin. However, when UV light is applied, melting of the hairpin structure (duplex) is induced via trans-to-cis conversion, thereby changing conformation of the aptamer and making the aptamer free to bind to and inhibit its target thrombin. By using standard clotting assays, we measured the IC 200 of various probe designs in both states and concluded the feasibility of using photon energy to temporally and spatially regulate these enzymatic reactions. Thus, we can report the development of DNA probes in the form of photon-controllable (thrombin) inhibitors, termed PCIs, and we expect that this approach will be highly beneficial in future biomedical and pharmaceutical applications.anticoagulation ͉ aptamer ͉ enzyme inhibitor ͉ photo controllable ͉ thrombine O ver the last decade, extensive research has been devoted to the study of phototransformable molecules based on photochromism chemistry. This science has been applied to photooptical technology and such photomodulated devices as eyeglasses called Transitions (1-4). A photochromic compound has 2 molecular states: stable and relatively unstable. The 2 states are interchangeable by the effect of irradiation using different wavelengths and differ from one another in terms of both physical and chemical properties. The photoconversion mechanism can largely be divided into 3 transformation types: photochromic tautomerism, cis-trans isomerization, and photocyclization. Briefly, photoisomerization is a process in which molecular structural change between isomers is caused by photoexcitation. Therefore, because isomerization causes a conformational change that can change the overall structure of a molecule, cis-trans isomerization is an intriguing mechanism that can be used to regulate mechanical devices and biological reactions (5-8).As one of the most popular phototransformable molecules in use today, azobenzene and its derivatives belong to the cis-trans isomerization category and are composed of 2 phenyl rings linked by a NAN double bond (Fig. 1) (9). The 2 isomers can be switched with particular wavelengths of light: UV light at 365 nm, corresponding to the trans-to-cis conversion, and visible light at 465 nm, corresponding to the cis-to-trans isomerization. There are reports that demonstrate the possible applications of su...