Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model

Hobbs, Jennifer; Zakarija, Anaadriana; Cundiff, Deborah L.; Doll, Jennifer A.; Hymen, Emily; Cornwell, Mona; Crawford, Susan E.; Liu, Na; Signaevsky, Maxim; Soff, Gerald A.

doi:10.1016/s0049-3848(07)70126-3

Cited by 86 publications

(104 citation statements)

References 45 publications

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“…TF also stimulates HuDMEC migration and tubule formation/differentiation, although to a lesser extent, and appears not to be dose dependent or resulting from VEGF up-regulation. This is in agreement with studies demonstrating that soluble TF promotes EC migration and tubule formation [19] and that an alternatively spliced form of TF (asTF) induces tubule formation independently of VEGF or PAR signaling [20]. In vitro assays from the current study were carried out in the absence of activated factor VII (FVIIa), by using low levels of heat inactivated serum, and data indicate a direct role for TF signaling in EC migration and tubule formation, although the precise mechanisms mediating this response are as yet undetermined.…”

Section: Discussionsupporting

confidence: 92%

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

Bluff

Amarzguioui

Slattery

et al. 2010

Breast Cancer Res Treat

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Purpose: In breast cancer there is a correlation between tissue factor (TF) expression, angiogenesis and disease progression. TF stimulates tumour angiogenesis, in part, through up-regulation of vascular endothelial growth factor (VEGF). Therefore, this study aim ed to establish whether TF stimulates angiogenesis and tumour progression directly and independent of VEGF up-regulation.Methods: Initially the effects of TF and VEGF were assessed on endothelial cell migration (Boyden chamber) and differentiation (tubule formation on Matrigel). Susbequently MDA-MB-436 breast cancer cells, which produce high levels of both TF and VEGF (western blot analysis), were established in vivo, following which tumours were treated three times per week for three weeks with intra-tumoural injections of either anti-VEGF siRNA, anti-TF shRNA, the two treatments combined or relevant controls. 136.3+/-9.2 mm 3 vs control 400.4+/-32.7 mm 3 : p<0.005). Microvessel density, a measure of angiogenesis, was also significantly inhibited in all groups (MVD in control=29+/-2.9; TFshRNA=18+/-1.1; VEGFsiRNA=16.7+/-1.5; both=12+/-2.1; p<0.004), whereas the proliferative index of the tumours was only reduced in the TFshRNA treated groups (control=0.51+/-0.011; TFshRNA=0.41+/-0.014; VEGFsiRNA=0.49+/-0.013; both=0.41+/-0.004; p<0.008).Conclusions: These data suggest that TF has a direct effect on primary breast cancer growth and angiogenesis, and that specific inhibition of the TF signalling pathway has potential for the treatment of primary breast cancer.

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Section: Discussionsupporting

confidence: 92%

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

Bluff

Amarzguioui

Slattery

et al. 2010

Breast Cancer Res Treat

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“…In 2003, Bogdanov et al described an alternatively spliced form of TF (asTF), which lacks a transmembrane domain and is present as a soluble protein [1]. asTF is produced by various cell types [1][2][3] and was reported to be present in human plasma, suggesting that asTF is secreted [1]. At present, the coagulant properties of asTF are disputed.…”

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confidence: 99%

“…Although recombinant asTF shortened the clotting time of platelet poor plasma [1], asTF was enriched in human thrombi [1] and triggered activation of factor (F)X when secreted by human umbilical vein endothelial cells (HUVEC) [4], asTF expressed by human embryonic kidney (HEK) cells failed to activate FX [5]. To further explore the putative role of asTF in coagulation, we studied the procoagulant properties of asTF cloned from HUVEC in an expression model of MIA PaCa-2 cells, a human pancreatic TF-deficient cell line [2,[6][7][8]. Using these cells, confounding factors such as concurrent expression of TF are excluded.…”

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confidence: 99%

“…Similar to our findings, asTF was present in cell lysates, absent in MP and culture supernatant and lacked procoagulant activity. Recently, Hobbs et al expressed asTF in MIA PaCa-2 cells [2]. They reported secretion of asTF in the conditioned medium, but found no shortening of a clotting time, again indicating that asTF lacks procoagulant activity.…”

mentioning

confidence: 99%

“…In contrast, when this asTF cDNA was expressed in MIA PaCa-2 cells, the asTF protein became detectable. Also several other pancreatic cells produce and secrete substantial quantities of asTF [2]. Last year, Hobbs et al reported a higher tumor mass in mice injected with asTF-transfected MIA PaCa-2 cells, suggesting a role in tumor growth and angiogenesis.…”

mentioning

confidence: 99%

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Human alternatively spliced tissue factor is not secreted and does not trigger coagulation

Böing

Hau

Sturk

et al. 2009

Journal of Thrombosis and Haemostasis

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1-74) in patients (n = 68) with normal MP-TF activity (P = 0.028). In the group of 51 patients who presented with VTE, survival was significantly worse in patients with elevated MP-TF activity than in those with normal MP-TF activity (P = 0.010). In univariate analysis only tumour type, thrombosis and MP-TF activity were significantly associated with survival. In multivariate analysis, adjustment for tumour type, age and stage, did not affect the association between MP-TF activity and mortality (P < 0.015).The present study is the largest series of unselected patients with both cancer and VTE, in whom MP-TF activity has been measured in the acute phase of thrombosis. The strength of the present study is that we did not select for any tumour type but instead investigated all cancer patients who presented with acute VTE irrespective of the type of malignancy. We observed that MP-TF activity in cancer patients with VTE is higher than in matched cancer patients without VTE. This finding strongly supports previous observations of a relationship between elevated MP-TF activity and VTE in patients with cancer from small studies of selected cancer patients [1,[4][5][6].It is interesting that the large majority of patients who develop VTE during chemotherapy have normal MP-TF activity, suggesting that an acute thrombotic event itself is not the cause of an elevated MP-TF activity. Our data point to a contribution of cancer cells themselves as (in) direct cause of elevated MP-TF activity and ask for novel studies better designed to study prospectively the relationship between chemotherapy, elevated MP-TF activity and venous thrombosis. AcknowledgementsThis study was financially supported by a grant of the Dutch Cancer Foundation KWF/NKB UL-2006-3618. Disclosure of Conflict of InterestsThe authors state that they have no conflict of interest.

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Hemostatic complications of angiogenesis inhibitors in cancer patients

et al. 2008

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Tumor vasculature and tumor‐associated neo‐angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well‐known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.

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Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model

Cited by 86 publications

References 45 publications

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

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

Human alternatively spliced tissue factor is not secreted and does not trigger coagulation

Hemostatic complications of angiogenesis inhibitors in cancer patients

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