Ectopic Synthesis of Coagulation Factor VII in Breast Cancer Cells: Mechanisms, Functional Correlates, and Potential for a New Therapeutic Target

Koizume, Shiro; Miyagi, Yohei

doi:10.5772/21757

Cited by 3 publications

(7 citation statements)

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“…This is an unexpected result as it had previously been observed that TF does not contribute to cell proliferation under in vitro cell culture conditions [43] . Indeed, this study demonstrated that proliferation of breast cancer cells with high TF expression was not enhanced by exogenous supply of fVII [101] . To date, however, the mechanisms regulating differential cell growth between cells exposed to exogenously supplied fVII and ectopically synthesized fVII remain unclear.…”

Section: Inducible Expression Under Hypoxiamentioning

confidence: 87%

“…These studies revealed that fVII transcript levels are not enhanced in response to hypoxic stimuli in breast cancer cell lines with high fVII expression [100] . Conversely, fVII mRNA levels were inducible in the breast cancer cell line, MDA-MB-468 under CoCl2 stimuli [101] , suggesting a cell-type dependent induction of fVII.…”

Section: Inducible Expression Under Hypoxiamentioning

confidence: 97%

“…This indicates that the promoter region occupied by HIF2 is devoid of a hypoxia response element (HRE) [16,102] , suggesting that HRE-independent mechanisms are responsible for FVII activation under hypoxic conditions. Indeed, chromatin immunoprecipitation analysis with MDA-MB-468 cells revealed that HIF2 predominantly associates with the FVII promoter region [101] , as in the case of ovarian cancer cells [16] . Furthermore, this mechanism was synergistically induced following simultaneous exposure of ovarian cancer cells to hypoxic conditions and serum deprivation, via a HDAC4 (a class II histone deacetylase)-dependent pathway [102] .…”

Section: Inducible Expression Under Hypoxiamentioning

confidence: 99%

“…This may be particularly important in hypoxic cancer microenvironments, where the supply of fVII from the bloodstream is likely limited because of poor and aberrant vasculature. In addition, it was recently described that ectopically synthesized fVII can augment the growth of breast cancer cells [101] . This is an unexpected result as it had previously been observed that TF does not contribute to cell proliferation under in vitro cell culture conditions [43] .…”

Section: Inducible Expression Under Hypoxiamentioning

confidence: 99%

“…To date, the expression of fVII transcripts in response to hypoxia have been tested in several breast cancer cell lines [100,101] . These studies revealed that fVII transcript levels are not enhanced in response to hypoxic stimuli in breast cancer cell lines with high fVII expression [100] .…”

Section: Inducible Expression Under Hypoxiamentioning

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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Section: Inducible Expression Under Hypoxiamentioning

confidence: 87%

Section: Inducible Expression Under Hypoxiamentioning

confidence: 97%

Section: Inducible Expression Under Hypoxiamentioning

confidence: 99%

Section: Inducible Expression Under Hypoxiamentioning

confidence: 99%

Section: Inducible Expression Under Hypoxiamentioning

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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Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancer

et al. 2015

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BackgroundElucidation of the molecular mechanisms by which cancer cells overcome hypoxia is potentially important for targeted therapy. Complexation of hypoxia-inducible factors (HIFs) with aryl hydrocarbon receptor nuclear translocators can enhance gene expression and initiate cellular responses to hypoxia. However, multiple molecular mechanisms may be required for cancer cells to adapt to diverse microenvironments. We previously demonstrated that a physical interaction between the ubiquitously expressed transcription factor Sp1 and HIF2 is a major cause of FVII gene activation in poor prognostic ovarian clear cell carcinoma (CCC) cells under hypoxia. Furthermore, it was found that FVII activation is synergistically enhanced when serum-starved cells are cultured under hypoxic conditions. In this study, we investigated whether HIFs and transcription factor Sp1 cooperate to activate multiple genes in CCC cells under conditions of serum starvation and hypoxia (SSH) and then contribute to malignant phenotypes.MethodsTo identify genes activated under hypoxic conditions in an Sp1-dependent manner, we first performed cDNA microarray analyses. We further investigated the molecular mechanisms of synergistic gene activations including the associated serum factors by various experiments such as real-time RT-PCR, western blotting and chromatin immunoprecipitation. The study was further extended to animal experiments to investigate how it contributes to CCC progression in vivo.ResultsICAM1 is one such gene dramatically induced by SSH and is highly induced by SSH and its synergistic activation involves both the mTOR and autonomously activated TNFα-NFκB axes. We identified long chain fatty acids (LCFA) as a major class of lipids that is associated with albumin, a serum factor responsible for synergistic gene activation under SSH. Furthermore, we found that ICAM1 can be induced in vivo to promote tumor growth.ConclusionSp1 and HIFs collaborate to activate genes required for the adaptation of CCC cells to severe microenvironments, such as LCFA starvation and hypoxia. This study highlights the importance of transcriptional regulation under lipid starvation and hypoxia in the promotion of CCC tumor growth.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0351-z) contains supplementary material, which is available to authorized users.

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Tissue Factor-Expressing Tumor Cells Can Bind to Immobilized Recombinant Tissue Factor Pathway Inhibitor under Static and Shear Conditions In Vitro

et al. 2015

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Mammary tumors and malignant breast cancer cell lines over-express the coagulation factor, tissue factor (TF). High expression of TF is associated with a poor prognosis in breast cancer. Tissue factor pathway inhibitor (TFPI), the endogenous inhibitor of TF, is constitutively expressed on the endothelium. We hypothesized that TF-expressing tumor cells can bind to immobilized recombinant TFPI, leading to arrest of the tumor cells under shear in vitro. We evaluated the adhesion of breast cancer cells to immobilized TFPI under static and shear conditions (0.35 – 1.3 dyn/cm2). We found that high-TF-expressing breast cancer cells, MDA-MB-231 (with a TF density of 460,000/cell), but not low TF-expressing MCF-7 (with a TF density of 1,400/cell), adhered to recombinant TFPI, under static and shear conditions. Adhesion of MDA-MB-231 cells to TFPI required activated factor VII (FVIIa), but not FX, and was inhibited by a factor VIIa-blocking anti-TF antibody. Under shear, adhesion to TFPI was dependent on the TFPI-coating concentration, FVIIa concentration and shear stress, with no observed adhesion at shear stresses greater than 1.0 dyn/cm2. This is the first study showing that TF-expressing tumor cells can be captured by immobilized TFPI, a ligand constitutively expressed on the endothelium, under low shear in vitro. Based on our results, we hypothesize that TFPI could be a novel ligand mediating the arrest of TF-expressing tumor cells in high TFPI-expressing vessels under conditions of low shear during metastasis.

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Ectopic Synthesis of Coagulation Factor VII in Breast Cancer Cells: Mechanisms, Functional Correlates, and Potential for a New Therapeutic Target

Cited by 3 publications

References 44 publications

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

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

Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancer

Tissue Factor-Expressing Tumor Cells Can Bind to Immobilized Recombinant Tissue Factor Pathway Inhibitor under Static and Shear Conditions In Vitro

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