title: The cell-membrane prothrombinase, fibrinogen-like protein 2, promotes angiogenesis and tumor development.
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.
authors.affiliation: Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1); Hematology Laboratory, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel. Electronic address: erabi@clalit.org.il.
authors.forename: Esther
authors.initials: E
authors.lastname: Rabizadeh
authors.affiliation: Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1). Electronic address: izhackch@clalit.org.il.
authors.forename: Izhack
authors.initials: I
authors.lastname: Cherny
authors.affiliation: Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1). Electronic address: doronle@clalit.org.il.
authors.forename: Doron
authors.initials: D
authors.lastname: Lederfein
authors.affiliation: Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1). Electronic address: shanyshnush@walla.com.
authors.forename: Shany
authors.initials: S
authors.lastname: Sherman
authors.affiliation: Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1). Electronic address: nataliabi@clalit.org.il.
authors.forename: Natalia
authors.initials: N
authors.lastname: Binkovsky
authors.affiliation: Pathology Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel. Electronic address: blyrosenblat@clalit.org.il.
authors.forename: Yevgenia
authors.initials: Y
authors.lastname: Rosenblat
authors.affiliation: Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1); Thrombosis and Hemostasis Unit, Hematology Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel(1). Electronic address: aidai@clalit.org.il.
authors.forename: Aida
authors.initials: A
authors.lastname: Inbal
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: C095202:FGL2 protein, human; D034741:RNA, Small Interfering; D005340:Fibrinogen; D013925:Thromboplastin; D013917:Thrombin
keywords: Angiogenesis; Fibrinogen-like protein 2; Tumorigenesis