title: The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice.
abstract: Human tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits the plasmin- and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion, and metastasis. To directly assess its role in tumor growth and metastasis in vivo, we stably transfected HT-1080 fibrosarcoma cells expressing either fully active wild-type human TFPI-2 (WT) or inactive R24Q TFPI-2 (QT) and examined their ability to form tumors and metastasize in athymic mice in comparison to mock-transfected cells (MT). MT and QT fibrosarcoma tumors grew 2 to 3 times larger than WT tumors. Tumor metastasis was confined to the lung and was observed in 75% of mice treated with either MT or QT cells, whereas only 42% of mice treated with WT cells developed lung metastases. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of each tumor group revealed 3- to 6-fold lower levels of murine vascular endothelial growth factor gene expression in WT tumors in relation to either MT or QT tumors. Comparative tumor gene expression analysis revealed that several human genes implicated in oncogenesis, invasion, metastasis, apoptosis, and angiogenesis had significantly altered levels of expression in WT tumors. Our collective data demonstrate that secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis in vivo by regulating pericellular extracellular matrix (ECM) remodeling and angiogenesis.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Hitendra Singh
authors.initials: HS
authors.lastname: Chand
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Duan
authors.initials: D
authors.lastname: Ma
authors.forename: Hector David
authors.initials: HD
authors.lastname: Inzunza
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kamei
authors.forename: Donald
authors.initials: D
authors.lastname: Foster
authors.forename: Steven
authors.initials: S
authors.lastname: Brodie
authors.forename: Walter
authors.initials: W
authors.lastname: Kisiel
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics* / Q000473:pathology* / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D017354:Point Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D006023:Glycoproteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C021240:tissue-factor-pathway inhibitor 2