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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
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Inhibition of tissue factor signaling suppresses tumor growth

Henri H Versteeg1, Florence Schaffner, Marjolein Kerver

  • 1Department of Immunology, SP258, Scripps Research Institute, La Jolla, CA 92037, USA.

Blood
|September 29, 2007
PubMed

Insights

Direct tissue factor (TF) signaling, not just its role in coagulation, drives primary tumor growth. Inhibiting TF signaling pathways, particularly TF-PAR2, shows significant potential for cancer therapy with minimal impact on blood clotting.

Area of Science:

  • Oncology
  • Hematology
  • Molecular Biology

Background:

  • Tissue factor (TF) plays a known role in cancer progression and thrombosis.
  • The direct signaling functions of TF in cancer remain less understood.
  • TF's involvement in primary tumor growth requires further elucidation.

Purpose of the Study:

  • To investigate how direct TF signaling pathways contribute to primary tumor growth.
  • To differentiate the effects of inhibiting TF coagulation versus TF signaling.
  • To explore TF's interaction with integrins and PAR2 in cancer cells.

Main Methods:

  • Utilized isotype-matched monoclonal antibodies (mAbs) targeting TF: Mab-5G9 (inhibits coagulation) and Mab-10H10 (inhibits direct signaling).
  • Assessed TF-VIIa signaling, PAR2 activation, and TF-integrin interactions in epithelial, endothelial, and breast cancer cells.
  • Evaluated the in vivo antitumor efficacy of Mab-10H10 and PAR2 inhibition in human xenograft models.

Main Results:

  • Mab-10H10 blocked TF-VIIa mediated PAR2 activation and disrupted TF-integrin interactions.
  • TF association with alpha3beta1 integrin in breast cancer cells was constitutive and blocked by Mab-10H10.
  • Mab-10H10 demonstrated significant antitumor activity in vivo, comparable or superior to Mab-5G9.
  • Blocking PAR2 signaling also attenuated breast tumor growth.

Conclusions:

  • Tumor cell TF-PAR2 signaling is critical for tumor growth.
  • Targeting direct TF signaling pathways offers a promising therapeutic strategy for cancer.
  • Anti-TF strategies can be developed for cancer therapy with limited impact on hemostasis.

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