Overexpression of Alternatively Spliced Tissue Factor Induces the Pro-Angiogenic Properties of Murine Cardiomyocytic HL-1 Cells

Eisenreich, Andreas; Boltzen, Ulrike; Malz, Ronny; Schultheiss, Heinz‐Peter; Rauch, Ursula

doi:10.1253/circj.cj-10-0783

Cited by 26 publications

(58 citation statements)

References 37 publications

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“…Our findings are in agreement with those of other groups who recently reported upregulation of such proangiogenic molecules as VEGF, basis fibroblast growth factor (bFGF) and Cyr61 as a result of masTF overexpression in murine cardiomyocytes (23,36); the VEGFindependent nature of masTF-elicited effects in the sprouting assay and the gene array analysis suggest that murine ECs may react to masTF in ways not fully identical to those observed in cardiac tissue (Figures 4, 5). Cxcl2 (a gene analogous to Il-8) encodes a major inflammatory chemokine involved in the recruitment of inflammatory cells (37,38), whereas Csf-1 production by stromal cells has been linked to the increased recruitment of tumor-associated macrophages and propagation of metastases (39).…”

Section: Discussionsupporting

confidence: 93%

“…Thus, hasTF may be of interest in the field of anticancer therapies targeting neovascularization. Intriguingly, it was recently reported that overexpression of masTF in murine cardiomyocytes elicited increased production of promigratory and proangiogenic factors by these cells, although the molecular mechanisms underlying these effects of masTF were not fully ascertained (23). Because murine models comprise the preferred in vivo platform for cancer and cardiovascular research, it is imperative to determine whether masTF is a functional homolog of hasTF, especially with regard to nonproteolytic, integrin-mediated events promoting vessel growth.…”

Section: Introductionmentioning

confidence: 99%

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Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

Godby

Berg

Srinivasan

et al. 2012

Mol Med

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This study was performed to determine whether murine alternatively spliced tissue factor (masTF) acts analogously to human alternatively spliced tissue factor (hasTF) in promoting neovascularization via integrin ligation. Immunohistochemical evaluation of a spontaneous murine pancreatic ductal adenocarcinoma model revealed increased levels of masTF and murine full-length tissue factor (mflTF) in tumor lesions compared with benign pancreas; furthermore, masTF colocalized with mflTF in spontaneous aortic plaques of Ldlr -/-mice, indicating that masTF is likely involved in atherogenesis and tumorigenesis. Recombinant masTF was used to perform in vitro and ex vivo studies examining its integrin-mediated biologic activity. Murine endothelial cells (ECs) rapidly adhered to masTF in a β3-dependent fashion. Using adult and embryonic murine ECs, masTF potentiated cell migration in transwell assays. Scratch assays were performed using murine and primary human ECs; the effects of masTF and hasTF were comparable in murine ECs, but in human ECs, the effects of hasTF were more pronounced. In aortic sprouting assays, the potency of masTF-triggered vessel growth was undistinguishable from that observed with hasTF. The proangiogenic effects of masTF were found to be Ccl2-mediated, yet independent of vascular endothelial growth factor. In murine ECs, masTF and hasTF upregulated genes involved in inflammatory responses; murine and human ECs stimulated with masTF and hasTF exhibited increased interaction with murine monocytic cells under orbital shear. We propose that masTF is a functional homolog of hasTF, exerting some of its key effects via β3 integrins. Our findings have implications for the development of murine models to examine the interplay between blood coagulation, atherosclerosis and cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

Godby

Berg

Srinivasan

et al. 2012

Mol Med

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“…This induced angiogenesis in vitro and in vivo independent of PAR-2 (24 ). We also showed that asTF induced the proangiogenic potential and proliferation rate of immortalized cardiomyocytes in a PAR-2-independent manner (10 ). Moreover, we found asTF to induce chemotaxis of human monocytic THP-1 leukemia cells as well as cell proliferation of A549 lung cancer cells (2,10 ).…”

Section: Impact Of Tf Isoforms On Signaling In Cancermentioning

confidence: 52%

“…In contrast to flTF, asTF was demonstrated to mediate cell signaling independently of PAR-2 (10,21,24 ). In 2009, van den Berg and colleagues found that asTF directly binds to ␤3 and ␤1 integrins.…”

Section: Impact Of Tf Isoforms On Signaling In Cancermentioning

confidence: 99%

“…Because of alternative splicing TF is expressed in 3 mRNA splice variants: full-length (fl)TF, alternatively spliced (as)TF, and a third variant named TF-A. Translation of flTF and asTF mRNA splice variants leads to the generation of the flTF isoform, a membrane-bound and highly procoagulant protein (8 ), and soluble asTF with low prothrombogenic potential but strong proangiogenic, cell proliferationfacilitating, and prosurvival activities (2,9,10 ). The TF-A mRNA splice variant is not translated to a protein ( Fig.…”

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confidence: 99%

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Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

2016

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BACKGROUND:Tissue factor (TF) is an evolutionary conserved glycoprotein that plays an important role in the pathogenesis of cancer. TF is expressed in 2 naturally occurring protein isoforms, membrane-bound full-length (fl)TF and soluble alternatively spliced (as)TF. Both isoforms have been shown to affect a variety of pathophysiologically relevant functions, such as tumor-associated angiogenesis, thrombogenicity, tumor growth, and metastasis. Therefore, targeting TF either by direct inhibition or indirectly, i.e., on a posttranscriptional level, offers a novel therapeutic option for cancer treatment.CONTENT: In this review we summarize the latest findings regarding the role of TF and its isoforms in cancer biology. Moreover, we briefly depict and discuss the therapeutic potential of direct and/or indirect inhibition of TF activity and expression for the treatment of cancer.

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The role of tissue factor isoforms in cancer biology

Leppert

Eisenreich

2014

Int. J. Cancer

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Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally occurring protein isoforms, membrane-bound "full-length" (fl)TF and soluble alternatively spliced (as)TF. The TF isoform expression is differentially modulated on post-transcriptional level via regulatory factors, such as serine/arginine-rich (SR) proteins, SR protein kinases and micro (mi)RNAs. Both isoforms mediate a variety of physiologic-and pathophysiologic-relevant functions, such as thrombogenicity, angiogenesis, cell signaling, tumor cell proliferation and metastasis. In this review, we will depict the main mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Moreover, we will summarize and discuss the latest findings regarding the role of TF and its isoforms in cancer biology.Tissue factor (TF) is a glycoprotein and an evolutionary conserved member of the Class II cytokine receptor family, which was found in different species, such as human, mouse, rat, fish as well as in Drosophila melanogaster and mosquitos. 1-3 TF is expressed in two natural occurring protein isoforms, full-length (fl)TF and alternatively spliced (as)TF. [4][5][6] In human, flTF consists of a short intracellular domain (21 amino acids), a transmembrane domain (23 amino acids) and an extracellular domain (219 amino acids). 7 flTF is anchored to the cell membrane. 7,8 The primary function of flTF is the initiation of the blood coagulation cascade. 2,7,8 Beside this, flTF plays an important role in a variety of other biological processes, such as protease-activated receptor (PAR-)2-mediated cell signaling and tumor progression. 2,9,10 Due to alternative splicing the fifth exon of the primary TF transcript is excluded. 5,7 Translation of this messenger (m)RNA splice variant leads to the generation of asTF on protein level. asTF lacks the transmembrane domain and is therefore soluble. 7 Compared with flTF, asTF exhibits low prothrombogenic potential. 4,7,8 However, this isoform was recently linked more closely to angiogenesis, survival and cell growth. 3,[11][12][13][14] Post-transcriptional expression control regulate a variety of biologic functions, such as tumor cell invasion, metastasis and angiogenesis in cancer as well as in other settings. [15][16][17][18] Two major mechanisms modulate post-transcriptional expression: micro (mi)RNAs and alternative splicing processes. 16 In this review, we will discuss the latest findings regarding the impact of TF and its isoforms on cancer biology with special focus on pathophysiologic-relevant functions, such as thrombogenicity, tumor cell growth and angiogenesis. Moreover, we will shed light on the mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Cancer-Related Stimulation of TF ExpressionSeveral stimuli, such as hypoxia, vascular endothelial growth factor (VEGF) and the proinflammatory cytokine tumor necrosis fact...

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Overexpression of Alternatively Spliced Tissue Factor Induces the Pro-Angiogenic Properties of Murine Cardiomyocytic HL-1 Cells

Cited by 26 publications

References 37 publications

Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

The role of tissue factor isoforms in cancer biology

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