Role of Alternatively Spliced Tissue Factor in Pancreatic Cancer Growth and Angiogenesis

Maxim Signaevsky; Jennifer Hobbs; Jennifer Doll; Na Liu; Gerald A. Soff

doi:10.1055/s-2008-1079256

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2008; 34(2): 161-169
DOI: 10.1055/s-2008-1079256

Role of Alternatively Spliced Tissue Factor in Pancreatic Cancer Growth and Angiogenesis

Maxim Signaevsky¹ , Jennifer Hobbs² , Jennifer Doll³ , Na Liu¹ , Gerald A. Soff¹

¹Division of Hematology/Oncology, SUNY Downstate Medical Center, Brooklyn, New York
²St. Jude Children's Research Hospital, Memphis, Tennessee
³Feinberg School of Medicine at Northwestern University, Chicago, Illinois

Abstract

ABSTRACT

Increased tissue factor (TF) expression is observed in many types of cancer, associated with more aggressive disease, and in thrombosis. The mechanism by which TF promotes tumor growth remains unclear. Anticoagulation has been shown to result in a trend toward improved survival; no direct antitumor effect has been shown in cancer patients. Alternatively spliced tissue factor (asTF) was recently described, in which exon 5 is deleted. Because of a frame-shift in exon 6, the transmembrane and cytoplasmic domains are replaced with a unique COOH-terminal domain, making asTF soluble. Both alternatively spliced human tissue factor (asHTF) and full-length tissue factor (flTF) are expressed in human pancreatic cancer lines and in pancreatic cancer specimens. We studied the role of asHTF and flTF in a mouse model of pancreatic cancer. Although lacking procoagulant activity, asTF promotes primary growth of human pancreatic cancer cells in mice and augments tumor-associated angiogenesis. This body of work suggests a new paradigm for the role of TF in pancreatic cancer: that asHTF contributes to cancer growth, independent of procoagulant activity.

KEYWORDS

Alternatively spliced human tissue factor - tissue factor - cancer progression - metastasis - angiogenesis

Full Text

References

REFERENCES

1 Broze G JJ. The tissue factor pathway of coagulation. In: Loscalzo J, Schafer A Thrombosis and Hemorrhage. Philadelphia, PA; Lippincott Williams & Wilkins 2003: 62-80
2 Morrissey J H. Tissue factor: a key molecule in hemostatic and nonhemostatic systems. Int J Hematol. 2004; 79 103-108
3 Mackman N. Alternatively spliced tissue factor—one cut too many?. Thromb Haemost. 2007; 97 5-8
4 Eilertsen K E, Osterud B. Tissue factor: (patho)physiology and cellular biology. Blood Coagul Fibrinolysis. 2004; 15 521-538
5 Donati M B, Falanga A. Pathogenetic mechanisms of thrombosis in malignancy. Acta Haematol. 2001; 106 18-24
6 Falanga A. Thrombosis and malignancy: an underestimated problem. Haematologica. 2003; 88 607-610
7 Khorana A A, Fine R L. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004; 5 655-663
8 Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005; 6 401-410
9 Kakkar A K, Lemoine N R, Scully M F, Tebbutt S, Williamson R C. Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg. 1995; 82 1101-1104
10 Bogdanov V Y, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med. 2003; 9 458-462
11 Bogdanov V Y, Kirk R I, Miller C et al.. Identification and characterization of murine alternatively spliced tissue factor. J Thromb Haemost. 2006; 4 158-167
12 Ruf W, Schullek J R, Stone M J, Edgington T S. Mutational mapping of functional residues in tissue factor: identification of factor VII recognition determinants in both structural modules of the predicted cytokine receptor homology domain. Biochemistry. 1994; 33 1565-1572
13 Szotowski B, Antoniak S, Poller W, Schultheiss H P, Rauch U. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res. 2005; 96 1233-1239
14 Censarek P, Bobbe A, Grandoch M, Schror K, Weber A A. Alternatively spliced human tissue factor (asHTF) is not pro-coagulant. Thromb Haemost. 2007; 97 11-14
15 Hobbs J E, Zakarija A, Cundiff D L et al.. Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model. Thromb Res. 2007; 120(Suppl 2) S13-S21
16 Buller H R, van Doormaal F F, van Sluis G L, Kamphuisen P W. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost. 2007; 5(Suppl 1) 246-254
17 Rickles F R, Patierno S, Fernandez P M. Tissue factor, thrombin, and cancer. Chest. 2003; 124 58S-68S
18 Khorana A A, Ahrendt S A, Ryan C K et al.. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res. 2007; 13 2870-2875
19 Tesselaar M E, Romijn F P, Van Der Linden I K, Prins F A, Bertina R M, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?. J Thromb Haemost. 2007; 5 520-527
20 Ott I, Fischer E G, Miyagi Y, Mueller B M, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol. 1998; 140 1241-1253
21 Versteeg H H, Spek C A, Slofstra S H, Diks S H, Richel D J, Peppelenbosch M P. FVIIa:TF induces cell survival via G12/G13-dependent Jak/STAT activation and BclXL production. Circ Res. 2004; 94 1032-1040
22 Ruf W. Tissue factor and PAR signaling in tumor progression. Thromb Res. 2007; 120(Suppl 2) S7-S12
23 Bromberg M E, Konigsberg W H, Madison J F, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci U S A. 1995; 92 8205-8209
24 Abe K, Shoji M, Chen J et al.. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci U S A. 1999; 96 8663-8668
25 Palumbo J S, Degen J L. Mechanisms linking tumor cell-associated procoagulant function to tumor metastasis. Thromb Res. 2007; 120(Suppl 2) S22-S28
26 Bobek V, Kovarik J. Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother. 2004; 58 213-219
27 Hembrough T A, Swartz G M, Papathanassiu A et al.. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res. 2003; 63 2997-3000
28 Mueller B M, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest. 1998; 101 1372-1378
29 Bromberg M E, Sundaram R, Homer R J, Garen A, Konigsberg W H. Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule. Thromb Haemost. 1999; 82 88-92
30 Versteeg H H, Schaffner F, Kerver M et al.. Inhibition of tissue factor signaling suppresses tumor growth. Blood. 2008; 111 190-199
31 Palumbo J S, Talmage K E, Massari J V et al.. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood. 2007; 110 133-141
32 Smorenburg S M, Hettiarachchi R J, Vink R, Buller H R. The effects of unfractionated heparin on survival in patients with malignancy—a systematic review. Thromb Haemost. 1999; 82 1600-1604
33 Smorenburg S M, Vink R, Otten H M, Swaneveld F, Buller H R. The effects of vitamin K-antagonists on survival of patients with malignancy: a systematic analysis. Thromb Haemost. 2001; 86 1586-1587
34 Lee A Y, Levine M N, Baker R I et al.. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003; 349 146-153
35 Lee A Y, Rickles F R, Julian J A et al.. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005; 23 2123-2129
36 Kakkar A K, Levine M N, Kadziola Z et al.. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004; 22 1944-1948
37 Kakkar A K. Thrombosis and cancer. Hematol J. 2004; 5(Suppl 3) S20-S23
38 Klerk C P, Smorenburg S M, Otten H M et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005; 23 2130-2135
39 Nitori N, Ino Y, Nakanishi Y et al.. Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2005; 11 2531-2539
40 Haas S L, Jesnowski R, Steiner M et al.. Expression of tissue factor in pancreatic adenocarcinoma is associated with activation of coagulation. World J Gastroenterol. 2006; 12 4843-4849

Gerald J SoffM.D.

Division of Hematology/Oncology, SUNY Downstate Medical Center

450 Clarkson Ave., Box 20, Brooklyn, NY 11203

Email: gsoff@downstate.edu