Tissue factor associates with survival and regulates tumour progression in osteosarcoma.

Abstract

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.

• Authors: Chris Tieken, Michiel C Verboom, Wolfram Ruf, Hans Gelderblom, Judith V M G Bovée, Pieter H Reitsma, Anne-Marie Cleton-Jansen, Henri H Versteeg
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 115 Issue 5 Pg. 1025-33 (05 02 2016) ISSN: 2567-689X [Electronic] Germany
• PMID: 26763081 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• RNA, Neoplasm
• Thromboplastin

Topics

• Adolescent
• Animals
• Bone Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Child
• Disease-Free Survival
• Female
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Male
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness
• Osteosarcoma (genetics, metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Thromboplastin (antagonists & inhibitors, genetics, metabolism)
• Young Adult