The cell-membrane prothrombinase, fibrinogen-like protein 2, promotes angiogenesis and tumor development

Esther Rabizadeh, Izhack Cherny, Doron Lederfein, Shany Sherman, Natalia Binkovsky, Yevgenia Rosenblat, Aida Inbal

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28 Scopus citations

Abstract

The aim of the study was to further investigate the role of fibrinogen-like protein 2 (FGL-2), a transmembrane prothrombinase that directly cleaves prothrombin to thrombin, in angiogenesis and tumor development and the mechanism(s) underlying these processes. To study angiogenesis HUVEC clones with decreased fgl-2 mRNA were generated by specific siRNA. To study tumorigenesis SCID mice were implanted with intact (wild type) and fgl-2-silenced PC-3 clones. IFN-γ treated HUVEC expressing increased fgl-2 mRNA exhibited significant capillary sprouting that was not inhibited by hirudin, whereas fgl-2 silencing completely inhibited blood-vessel formation. Tumors (poorly differentiated carcinoma) developed in all 12 mice injected with wild type PC-3 compared with 8/12 mice injected with the fgl-2-silenced PC-3 clone. The tumors developed by fgl-2-silenced PC-3 clones were smaller and less aggressive and contained significantly fewer blood vessels (p < 0.05). All tumors' sections were negative for thrombin staining, indicating that FGL-2-induced tumorigenesis was not mediated by thrombin. In fgl-2-silenced tumors there was a decrease in fgl-2 mRNA (p = 0.02) and ERK1/2 phosphorylation (p < 0.05) by 80% and a 20%, respectively. The mechanism underlying these processes, studied in PC-3 clones, revealed that fgl-2 silencing was associated with a 65% decrease in FGF-2 mRNA (p < 0.01) and a 30% down regulation of ERK1/2 phosphorylation (p < 0.05). Together, these results suggest that FGL-2 mediates angiogenesis and tumorigenesis not by thrombin-mediated mechanism but rather through FGF-2/ERK signaling pathway. FGL-2 may serve as a valuable therapeutic target in the future.

Original languageEnglish
Pages (from-to)118-124
Number of pages7
JournalThrombosis Research
Volume136
Issue number1
DOIs
StatePublished - 1 Jul 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Ltd.

Funding

This work was supported by research funding from Nufar (grant # 44776 ), Chief Scientist, Ministry of Health, Israel. We would like to thank Eti Melai RN, MA for her assistance in the project.

FundersFunder number
Ministry of Health, State of Israel

    Keywords

    • Angiogenesis
    • Fibrinogen-like protein 2
    • Tumorigenesis

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