Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

Bluff, Joanne E.; Amarzguioui, Mohammed; Slattery, J.; Reed, Malcolm; Brown, Nicola J.; Staton, Carolyn A.

doi:10.1007/s10549-010-1149-8

Cited by 9 publications

(12 citation statements)

References 34 publications

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“…These data are consistent with observations from other studies that demonstrate that in cancer and SMCs, TF's effects on angiogenesis are independent of VEGF. 43,44 In conclusion, we have identified a novel pathway by which TF promotes microvessel formation. Endogenous EC TF induces CCL2 secretion.…”

Section: Discussionmentioning

confidence: 76%

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Arderiu

Peña

Aledo

et al. 2011

ATVB

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Objective-Tissue factor (TF) triggers arterial thrombosis. TF is also able to initiate cellular signaling mechanisms leading to angiogenesis. Because high cardiovascular risk atherosclerotic plaques show significant angiogenesis, our objective was to investigate whether TF is able to trigger and stabilize atherosclerotic plaque neovessel formation. Methods and Results-In this study, we showed, by real-time confocal microscopy in 3-dimensional basement membrane cocultures, that TF in human microvascular endothelial cells (HMEC-1) and in human vascular smooth muscle cells (HVSMCs) plays an important role in the formation of capillary-like networks. TF silencing in endothelial cells and smooth muscle cells inhibits the formation of tube-like structures with stable phenotype. Using an in vivo model, we observed that TF inhibition in either HMEC-1 or HVSMCs reduced their shared ability to form new capillaries. The phenotypic changes induced by TF silencing were linked to reduced chemokine (C-C motif) ligand 2 (CCL2) expression in endothelial cells. Wound healing and chemotactic assays demonstrated that TF-induced release of CCL2 stimulated HVSMC migration to HMEC-1. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ cytokines Ⅲ endothelial function Ⅲ vascular biology A therosclerotic plaque angiogenesis, the outgrowth of new capillaries from preexisting vascular networks, is a pathological feature of advanced complicated plaques. 1,2 Interestingly, coronary type VI plaques, according to the American Heart Association classification, are those with higher amount of microvessels and those with higher risk of inducing a clinical cardiovascular event. 3 In advanced plaques, inflammatory cell infiltration and concomitant production of proangiogenic cytokines may be responsible for induction of uncontrolled neointimal microvessel proliferation resulting in production of immature and fragile neovessels. The final stage of microvessel formation occurs when maturation requires the formation of tight endothelial cell-tocell contacts, 4 the downregulation of endothelial proliferation, and the deposition of a basal lamina to which the endothelium tightly adheres, as well as the recruitment of supporting cells to the vessel wall, such as pericytes and smooth muscle cells (SMCs). 5,6 During angiogenesis, the communication between endothelial cells (ECs) and SMCs requires a precise temporal and spatial regulation of pro-and antiangiogenic molecules, but the process is not yet fully understood. Conclusion-Endogenous See accompanying article on page 2364In recent years, it has become clear that the angiogenesis process is highly dependent on components of the blood coagulation cascade. One of these proteins is tissue factor (TF). 7-9 TF is the cellular receptor and cofactor for blood coagulation factor VII (FVII). 10,11 In addition to its primary role in blood coagulation, accumulating evidence has transformed our view of TF from the cellular receptor for activated FVII (FVIIa) to a multifaceted transmembrane signaling receptor. The bioch...

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Section: Discussionmentioning

confidence: 76%

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Arderiu

Peña

Aledo

et al. 2011

ATVB

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“…An in vivo HKII shRNA delivery system should be developed for clinical application. For this, a lentiviral shRNA delivery system can be an option because of its long-term effect and high gene transduction efficiency in both dividing and nondividing cells (13). In the current study, we successfully inhibited HKII gene expression, decreased glucose uptake, and decreased HK activity with lentiviral vector-mediated HKII shRNA delivery.…”

Section: Discussionmentioning

confidence: 84%

“…However, siRNA is known to be degraded in cells within a few days. Contrary to siRNA, small hairpin RNA (shRNA) is integrated into chromosomal DNA and is constantly expressed to achieve prolonged gene silencing (13). The major advantage of the lentiviral shRNA system is that the shRNA can be delivered into both dividing and nondividing cells to achieve stable long-term effects on target gene silencing; therefore, it can be used for in vivo applications (14).…”

mentioning

confidence: 99%

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

et al. 2011

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The purpose of this study was to investigate the enhanced therapeutic effect of the combined use of shRNA (small hairpin RNA) therapy for the hexokinase II (HKII) gene and 131 I human sodium iodide symporter (hNIS) as a gene therapy for in vitro and in vivo treatment of anaplastic thyroid carcinoma cells (ARO) in an animal model. Methods: A recombinant lentivirus containing a plasmid with the hNIS gene driven by phosphoglycerate kinase promoter and green fluorescent protein (GFP) linked with an internal ribosome entry site sequence was produced. ARO cells were transfected with the virus and sorted by fluorescent activated cell sorting using GFP (ARO-NG). The messenger RNA expression of hNIS and GFP were evaluated with reverse-transcriptase polymerase chain reaction, and the function of hNIS was verified by 125 I uptake. The lentiviral vector expressing shRNA against HKII (Lenti-HKII shRNA) was constructed and used to infect ARO-NG cells. The effect of Lenti-HKII shRNA was evaluated by reverse-transcriptase polymerase chain reaction, 18 F-FDG uptake, and HK activity. An in vitro clonogenic assay was performed after Lenti-HKII shRNA therapy, 131 I therapy, and a combined therapy. The therapies were also applied in vivo to an animal model with an ARO-NG xenograft, and the effects were assessed with caliper measurements and 18 F-FDG PET. Results: ARO-NG cells showed an 125 I uptake 76-fold higher than the parent ARO cells. Compared with the uninfected ARO-NG cells, ARO-NG cells infected with Lenti-HKII shRNA had lower HKII messenger RNA expression, lower 18 F-FDG uptake, and HK activity. The proliferation of ARO-NG cells was inhibited by 131 I and Lenti-HKII shRNA therapies and further inhibited by the combined 131 I and Lenti-HKII shRNA therapy. Both the Lenti-HKII shRNA therapy and the 131 I therapy inhibited in vivo tumor growth in the tumor xenograft model. The combined Lenti-HKII shRNA and 131 I therapy resulted in a further decrease of tumor growth. Conclusion: Our results suggest that the combined HKII shRNA and 131 I therapy has a stronger antitumor effect than either the 131 I therapy or the HKII shRNA alone. Therefore, this combined therapy could be used as a powerful strategy for treating anaplastic thyroid carcinoma.

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“…Prior studies pointed to a role for TF in tumor progression (19)(20)(21). To explore whether asTF and flTF differentially contribute to BrCa progression, we analyzed asTF and flTF protein expression in a BrCa tissue array comprising specimens from 574 BrCa patients (22).…”

Section: Results Astf Expression Positively Correlates With Brca Gradmentioning

confidence: 99%

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

Kocatürk¹,

Berg²,

Tieken³

et al. 2013

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

126

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Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.regulated pre-mRNA processing | outside-in signaling I n breast cancer (BrCa), proteins that modulate splicing events such as ASF/SF2 and SR(Serine/Arginine-rich)p55, are frequently up-regulated and contribute to cell transformation (1, 2). BrCa cells exhibit specific alternative splicing signatures that were proposed as potential prognostic factors in BrCa (3). Alternative splicing of proteins, such as spleen tyrosine kinase (Syk), p53, phosphatase and tensin homolog (PTEN), chemokine (C-X-C motif) receptor 3 (CXCR3), and ras-related C3 botulinum toxin substrate 1 (Rac1) impacts BrCa cell behavior and therefore, disease progression (4-8).Full-length tissue factor (flTF) is the initiator of blood coagulation (9). Following vascular damage, flTF binds its ligand FVII(a), which triggers clot formation. Aside from subendothelial tissues, flTF is also abundant on cancer cells (9) and fuels tumor progression by modulating integrin α3β1 function, cell migration (10), and FVIIa-dependent protease activated receptor (PAR)2 activation, but flTF-β1 integrin complexation enhances PAR2 activation (11). flTF-dependent PAR2 activation results in the production of VEGF, CXCL1, and IL-8, thus promoting the angiogenic switch and consequently, tumor growth in vivo (10, 11).Alternative splicing of TF pre-mRNA results in the deletion of exon 5 and thus a frameshift in exon 6, yielding a transmembrane domain-lacking isoform that can be secreted (12). Human and murine alternatively spliced TF (asTF) contain novel C termini with poor homology to one another or any other protein, and the murine asTF C terminus is longer than that of human asTF (12,13). High expression of asTF in tumor cell lines suggests a role in tumor progression (10,14). Subcutaneous growth of pancreatic cancer cells overexpressing asTF results in larger and more vascularized tumors (15). We recently discovered that asTF induces angiogenesis, independent of PAR2 activation, by acting as an integrin ligand (16). Thus, flTF and asTF facilitate cellular signaling via ...

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Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

Cited by 9 publications

References 34 publications

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

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Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

Cited by 9 publications

References 34 publications

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Combined RNA Interference of Hexokinase II and 131I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

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Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma