Activation of Cancer Cell Migration and Invasion by Ectopic Synthesis of Coagulation Factor VII

Koizume, Shiro; Jin, Ming-shou; Miyagi, Etsuko; Hirahara, Fumiki; Nakamura, Yoshiyasu; Piao, Jinhua; Asai, Akio; Yoshida, Akira; Tsuchiya, Eiju; Ruf, Wolfram; Miyagi, Yohei

doi:10.1158/0008-5472.can-06-1803

Cited by 128 publications

(182 citation statements)

References 46 publications

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“…Thus, while under normal circumstances several components of the coagulation cascade are produced exclusively in the liver, and under control of vitamin K-regulated mechanisms [71], this requirement can be circumvented by cellular transformation. Indeed, production of coagulation factors VII and II has been reported to occur in hepatocyte-unrelated cancer cells [72,73]. This is important as vitamin K antagonists are often used in thromboprophylaxis, including in cancer, and it remains uncertain whether they are effective in suppressing coagulation factor production by cells harboring mutant oncogenes.…”

mentioning

confidence: 99%

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

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D’Asti

Meehan

et al. 2014

Thrombosis Research

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mentioning

confidence: 99%

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Magnus

D’Asti

Meehan

et al. 2014

Thrombosis Research

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“…This extravascular fVII may bind to TF, which is present on the surface of cancer cells. Notably, multiple breast cancer cells have been shown to ectopically synthesize fVII [16] . This fVII is functional [16] , suggesting that aberrantly synthesized fVII may also contribute to the malignant phenotypes of breast cancer.…”

Section: Topic Highlightmentioning

confidence: 99%

“…Notably, multiple breast cancer cells have been shown to ectopically synthesize fVII [16] . This fVII is functional [16] , suggesting that aberrantly synthesized fVII may also contribute to the malignant phenotypes of breast cancer. In this review, we summarize the recent progress in breast cancer biology associated with aberrant coagulation mechanisms.…”

Section: Topic Highlightmentioning

confidence: 99%

“…However, various cancer cells may ectopically express fVII [16] . Notably, multiple breast cancer cell lines constitutively synthesize high levels of the fVII transcript [16] .…”

Section: Ectopic Expression Of Fvii In Breast Cancer Cellsmentioning

confidence: 99%

“…However, various cancer cells may ectopically express fVII [16] . Notably, multiple breast cancer cell lines constitutively synthesize high levels of the fVII transcript [16] . Cancer cells with fVII expression exhibit pro-coagulant activity as TFfVIIa complex is formed on the cell surface, suggesting that aberrantly synthesized fVII may be functionally active and contribute to breast cancer progression.…”

Section: Ectopic Expression Of Fvii In Breast Cancer Cellsmentioning

confidence: 99%

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Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets

Koizume

Miyagi

2014

WJCO

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Breast cancer is a leading cause of cancer death in women, worldwide. Fortunately, breast cancer is relatively chemosensitive, with recent advances leading to the development of effective therapeutic strategies, significantly increasing disease cure rate. However, disease recurrence and treatment of cases lacking therapeutic molecular targets, such as epidermal growth factor receptor 2 and hormone receptors, referred to as triple-negative breast cancers, still pose major hurdles in the treatment of breast cancer. Thus, novel therapeutic approaches to treat aggressive breast cancers are essential. Blood coagulation factor VII (fVII) is produced in the liver and secreted into the blood stream. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. TF is overexpressed in breast cancer tissues. The TF-fVII complex may be formed in the absence of injury, because fVII potentially exists in the tissue fluid within cancer tissues. The active form of this complex (TF-fVIIa) may stimulate the expression of numerous malignant phenotypes in breast cancer cells. Thus, the TF-fVII pathway is a potentially attractive target for breast cancer treatment. To date, a number of studies investigating the mechanisms by which TF-fVII signaling contributes to breast cancer progression, have been conducted. In this review, we summarize the mechanisms controlling TF and fVII synthesis and regulation in breast cancer cells. Our current understanding of the TF-fVII pathway as a mediator of breast cancer progression will be also described. Finally, we will discuss how this knowledge can be applied to the design of future therapeutic strategies. Key words: Breast cancer; Blood coagulation; Tissue factor; Coagulation factor VII; Gene regulation; Therapeutic strategy Core tip: Breast cancer is a worldwide problem. Difficulties with treating the disease and its recurrence persist due, in part, to a lack of therapeutic molecular targets. Blood coagulation factor VII (fVII) is generally produced in the liver. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. Formation of the TF-fVII complex causes contributes to the malignant phenotype of breast cancer cells. In this review, we summarize the breast cancer biology associated with the TF-fVII pathway. Further, we will discuss how these mechanisms can be targeted as therapeutics for this aggressive disease.Koizume S, Miyagi Y. Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets.

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Evidence for tissue factor phosphorylation and its correlation with protease‐activated receptor expression and the prognosis of primary breast cancer

Rydén

Grabau

Schaffner

et al. 2009

Intl Journal of Cancer

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Tissue factor (TF)‐mediated protease‐activated receptor (PAR)‐2 signaling is associated with a promigratory, invasive and proangiogenic phenotype in experimental models of breast cancer and has been mechanistically coupled to phosphorylation of the TF cytoplasmic domain (pTF). However, the clinical relevance of these findings is unknown. Here, we provide the first in vivo evidence of TF phosphorylation in experimental as well as clinical breast cancer tumors. pTF was demonstrated in MDA‐MB‐231 xenografts and in tumors from the MMTV‐PyMT transgene model of spontaneous murine breast adenocarcinoma. Tumors from PAR‐2–deficient transgenic mice were negative for pTF, thus linking pTF to PAR‐2 signaling. The clinical correlation between TF, pTF, PAR‐1, PAR‐2 and vascular endothelial growth factor (VEGF)‐A was determined by immunohistochemistry on tumors from a cohort of 172 consecutive primary breast cancer patients, with a median follow‐up time of 50 months. In 160 evaluable patient tumors, pTF was associated with TF (p = 0.01) and cancer cell expression of PAR‐1 (p = 0.001), PAR‐2 (p = 0.014) and VEGF‐A (p = 0.003) using χ2 test. PAR‐2 and VEGF‐A were coexpressed (p = 0.013) and associated with a more aggressive phenotype. Interestingly, all patients experiencing recurrences had tumors expressing pTF and PAR‐2, and pTF alone as well as coexpression of pTF and PAR‐2 were significantly correlated with shorter recurrence‐free survival (log rank test, p = 0.04 and p = 0.02, respectively). This study provides the first evidence to link PAR‐2 expression and TF phosphorylation to clinical data in human breast cancer. In conjunction with experimental tumor models, these data support an important role of TF‐PAR‐2 signaling in breast cancer recurrence.

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Activation of Cancer Cell Migration and Invasion by Ectopic Synthesis of Coagulation Factor VII

Cited by 128 publications

References 46 publications

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets

Evidence for tissue factor phosphorylation and its correlation with protease‐activated receptor expression and the prognosis of primary breast cancer

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