Inhibition of tissue factor signaling suppresses tumor growth

Henri H. Versteeg, Florence Schaffner, Marjolein Kerver, Helle H. Petersen, Jasimuddin Ahamed, Brunhilde Felding-Habermann, Yoshikazu Takada, Barbara M. Mueller, Wolfram Ruf

Research output: Contribution to journalArticle

225 Citations (Scopus)

Abstract

Coagulation activation by tissue factor (TF) is implicated in cancer progression, cancer-associated thrombosis and metastasis. The role of direct TF signaling pathways in cancer, however, remains incompletely understood. Here we address how TF contributes to primary tumor growth by using a unique pair of isotype-matched antibodies that inhibit either coagulation (monoclonal antibody [Mab]-5G9) or direct signaling (Mab-10H10). We demonstrate that the inhibitory antibody of direct TF-VIIa signaling not only blocks TF-VIIa mediated activation of PAR2, but also disrupts the interaction of TF with integrins. In epithelial and TF-expressing endothelial cells, association of TF with β1 integrins is regulated by TF extracellular ligand binding and independent of PAR2 signaling or proteolytic activity of VIIa. In contrast, α3β1 integrin association of TF is constitutive in breast cancer cells and blocked by Mab-10H10 but not by Mab-5G9. Mab-5G9 has antitumor activity in vivo, but we show here that Mab-10H10 is at least as effective in suppressing human xenograft tumors in 2 different models. Breast tumor growth was also attenuated by blocking PAR2 signaling. These results show that tumor cell TF-PAR2 signaling is crucial for tumor growth and suggest that anti-TF strategies can be applied in cancer therapy with minor impairment of TF-dependent hemostatic pathways.

Original languageEnglish (US)
Pages (from-to)190-199
Number of pages10
JournalBlood
Volume111
Issue number1
DOIs
StatePublished - Jan 1 2008

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Thromboplastin
Tumors
Growth
Neoplasms
Monoclonal Antibodies
Integrins
Factor VIIa
Coagulation
Chemical activation
Cells
Association reactions
Breast Neoplasms
Antibodies
Endothelial cells
Hemostatics
Heterografts
Thrombosis
Epithelium
Endothelial Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Versteeg, H. H., Schaffner, F., Kerver, M., Petersen, H. H., Ahamed, J., Felding-Habermann, B., ... Ruf, W. (2008). Inhibition of tissue factor signaling suppresses tumor growth. Blood, 111(1), 190-199. https://doi.org/10.1182/blood-2007-07-101048

Inhibition of tissue factor signaling suppresses tumor growth. / Versteeg, Henri H.; Schaffner, Florence; Kerver, Marjolein; Petersen, Helle H.; Ahamed, Jasimuddin; Felding-Habermann, Brunhilde; Takada, Yoshikazu; Mueller, Barbara M.; Ruf, Wolfram.

In: Blood, Vol. 111, No. 1, 01.01.2008, p. 190-199.

Research output: Contribution to journalArticle

Versteeg, HH, Schaffner, F, Kerver, M, Petersen, HH, Ahamed, J, Felding-Habermann, B, Takada, Y, Mueller, BM & Ruf, W 2008, 'Inhibition of tissue factor signaling suppresses tumor growth', Blood, vol. 111, no. 1, pp. 190-199. https://doi.org/10.1182/blood-2007-07-101048
Versteeg HH, Schaffner F, Kerver M, Petersen HH, Ahamed J, Felding-Habermann B et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood. 2008 Jan 1;111(1):190-199. https://doi.org/10.1182/blood-2007-07-101048
Versteeg, Henri H. ; Schaffner, Florence ; Kerver, Marjolein ; Petersen, Helle H. ; Ahamed, Jasimuddin ; Felding-Habermann, Brunhilde ; Takada, Yoshikazu ; Mueller, Barbara M. ; Ruf, Wolfram. / Inhibition of tissue factor signaling suppresses tumor growth. In: Blood. 2008 ; Vol. 111, No. 1. pp. 190-199.
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