Tissue factor associates with survival and regulates tumour progression in osteosarcoma

Chris Tieken; Michiel C. Verboom; Wolfram Ruf; Hans Gelderblom; Judith V. M. G. Bovée; Pieter H. Reitsma; Anne-Marie Cleton-Jansen; Henri H. Versteeg

doi:10.1160/TH15-07-0541

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 115(05): 1025-1033
DOI: 10.1160/TH15-07-0541

Endothelium and Angiogenesis

Schattauer GmbH

Tissue factor associates with survival and regulates tumour progression in osteosarcoma

Chris Tieken

¹Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, The Netherlands

,

Michiel C. Verboom

²Department of Clinical Oncology, Leiden University Medical Centre, Leiden, The Netherlands

,

Wolfram Ruf

³Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA

,

Hans Gelderblom

²Department of Clinical Oncology, Leiden University Medical Centre, Leiden, The Netherlands

,

Judith V. M. G. Bovée

⁴Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

,

Pieter H. Reitsma

¹Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, The Netherlands

,

Anne-Marie Cleton-Jansen

⁴Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

,

Henri H. Versteeg

¹Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, The Netherlands

› Institutsangaben

Abstract

Summary

Osteosarcoma is the most common primary malignant bone tumour. Patients often develop lung metastasis and have a poor prognosis despite extensive chemotherapy and surgical resections. Tissue Factor is associated with poor clinical outcome in a wide range of cancer types, and promotes angiogenesis and metastasis. The role of Tissue Factor in OS tumourigenesis is unknown. Fifty-three osteosarcoma pre-treatment biopsies and four osteosarcoma cell lines were evaluated for Tissue Factor expression, and a possible association with clinical parameters was investigated. Tissue Factor function was inhibited in an osteosarcoma cell line (143B) by shRNA knockdown or specific antibodies, and pro-tumourigenic gene expression, proliferation, matrigel invasion and transwell migration was examined. 143B cells were implanted in mice in the presence of Tissue Factor-blocking antibodies, and tumour volume, micro-vessel density and metastases in the lung were evaluated. Tissue Factor was highly expressed in 73.6 % of osteosarcoma biopsies, and expression associated significantly with disease-free survival. Tissue Factor was expressed in all four investigated cell lines. Tissue Factor was knocked down in 143B cells, which led to reduced expression of IL-8, CXCL-1, SNAIL and MMP2, but not MMP9. Tissue Factor knockdown or inhibition with antibodies reduced matrigel invasion. Tissue Factor antibodies limited 143B tumour growth in vivo, and resulted in decreased intra-tumoural micro-vessel density. Furthermore, lung metastasis from the primary tumour was significantly reduced. Thus, Tissue Factor expression in osteosarcoma reduces metastasis-free survival in patients, and increases pro-tumourigenic behaviour both in vitro and in vivo.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Osteosarcoma - coagulation - tumour - migration

Volltext

Referenzen

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