Does hypercoagulability awaken dormant tumor cells in the host?

Karpatkin, Simon

doi:10.1111/j.1538-7836.2004.01003.x

Cited by 15 publications

(11 citation statements)

References 42 publications

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“…10 Thrombin influences at least 2 important pathways in tumor cells. Thrombin-dependent PAR1 signaling induces proliferation of metastatic tumor cells, 11 and at low doses thrombin has been shown to enhance survival of tumor cells, 12 consistent with findings in other cell types. 13 Although at higher doses thrombin can induce apoptosis, one possible function of thrombin is thus modulation of apoptosis during metastasis.…”

Section: Coagulation and Metastasissupporting

confidence: 78%

Signaling of the Tissue Factor Coagulation Pathway in Angiogenesis and Cancer

Belting

Ahamed

Ruf

2005

ATVB

209

182

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Abstract-Activation of coagulation precedes or coincides with angiogenesis in wound healing and postischemic tissue regeneration. Advanced cancer is associated with a hypercoagulable state, and tissue factor expression by cancer cells has received widespread attention because of its significant contribution to the pathogenesis of cancer progression and metastasis. Our recent work demonstrates that tissue factor-mediated cellular signaling is relevant to cancer angiogenesis. Here we review the molecular mechanisms of tissue factor pathways in angiogenesis and tumorigenesis with emphasis on the intriguing role for tissue factor cytoplasmic domain signaling. Key Words: protease activated receptors Ⅲ metastasis Ⅲ integrin A ccumulating evidence has transformed our view of tissue factor (TF) from being a relatively simple protease coreceptor in the initiation phase of blood coagulation into a multi-facetted transmembrane signaling receptor involved in the regulation of angiogenesis, tumor growth, metastasis, and inflammation. TF-initiated coagulation generates thrombin, and this protease signals through the activation of a unique class of G protein-coupled protease activated receptors (PAR) 1, 3, and 4. 1 Signaling activities of TF may occur before or even independently of thrombin and fibrin generation, platelet activation, and blood clot formation. 2 See coverThese TF-dependent, upstream signaling events are also mediated by the PAR family of G-protein-coupled receptors, in particular PAR1 and PAR2. The TF-VIIa complex activates PAR2 and the product of initiation of coagulation, Xa, while still assembled in the transient ternary TF-VIIa-Xa complex, signals through PAR1 or PAR2. Both upstream PAR-mediated signaling and downstream coagulation events may thus contribute to cancer biology. In vivo, thrombin is generally considered to be the physiological activator of PARs in tumor biology and angiogenesis. We have recently provided in vivo evidence that PAR2, which is not cleaved by thrombin, is linked to TF-dependent angiogenesis. 3 Thus, broader roles of TF-initiated coagulation emerge in the regulation of cancer progression and angiogenesis. In this brief review, we will address pathways by which TF supports metastasis, tumor growth, and angiogenesis. The accumulating data indicate that TF expressed by tumors cells as well as host cells initiates direct or indirect signaling events that support tumor development by distinct mechanisms (Figure 1). Coagulation and MetastasisMetastasis is the result of multiple pathways that act in concert to provide tumor cells with the capacity to migrate, gain access to the blood stream or lymphatic vessels, and ultimately home to distant sites. Preclinical studies have clearly established that inhibition of platelet function correlates with decreased metastasis and tumor growth. Platelets facilitate metastasis by promoting tumor cell survival at the site of metastasis. 4 This involves protection of tumor cells from natural killer cell attack, increased tumor cell association with l...

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Section: Coagulation and Metastasissupporting

confidence: 78%

Signaling of the Tissue Factor Coagulation Pathway in Angiogenesis and Cancer

Belting

Ahamed

Ruf

2005

ATVB

209

182

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“…In this regard our results suggest the possibility that activation of the coagulation system by changes in cellular phenotype, hypoxia, or microinjury could set off a cascade of inflammatory and vascular events promoting the onset of malignant lesion. Indeed, Karpatkin and colleagues previously suggested a possible role of thrombin in cancer dormancy (41).…”

Section: Discussionmentioning

confidence: 99%

Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations

Magnus

Garnier

Meehan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Our study shows that the clotting protein tissue factor (TF) controls the state of tumor dormancy and does so in conjunction with recruitment of inflammatory cells and blood vessels. We show that indolent glioma cells remain harmless in mice unless rendered TF positive. Our work also demonstrates the ability of TF to indirectly influence the DNA of cancer cells by facilitating gene mutations and silencing. This ability is important because injury, cardiovascular disease, or other conditions may activate the clotting system and contribute to the awakening of occult cancer cells. This understanding also may suggest a prophylactic use of blood thinners in cases where dormant cancer cells and clotting are suspected to coexist (e.g., after surgery).

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“…Thrombin-dependent PAR1 signaling induces proliferation of metastatic tumor cells 35 and can be antiapoptotic. 36 Thrombin signaling through PAR1 influences tumor cell motility. For example, PAR1 can enhance a V b 5 integrin-dependent migration of tumor cells.…”

Section: Thrombin Pathways In Metastasismentioning

confidence: 99%

Thrombin Generation and the Pathogenesis of Cancer

Ruf

Mueller²

2006

Semin Thromb Hemost

161

121

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Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through fibrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain-deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment.

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Does hypercoagulability awaken dormant tumor cells in the host?

Cited by 15 publications

References 42 publications

Signaling of the Tissue Factor Coagulation Pathway in Angiogenesis and Cancer

Signaling of the Tissue Factor Coagulation Pathway in Angiogenesis and Cancer

Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations

Thrombin Generation and the Pathogenesis of Cancer

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