Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model. Thromb Res 2007;120 Suppl 2:S13-21
Date
11/21/2007Pubmed ID
18023707DOI
10.1016/S0049-3848(07)70126-3Scopus ID
2-s2.0-36049042581 (requires institutional sign-in at Scopus site) 80 CitationsAbstract
INTRODUCTION: Tissue Factor (TF) expression is observed in many types of cancer, associated with more aggressive disease, and thrombosis. Alternatively-spliced human tissue factor (asHTF) has recently been identified in which exon 5 is deleted. asHTF is soluble due to the substitution of the transmembrane and cytoplasmic domains of exon 6 with a unique COOH-terminal domain.
MATERIALS AND METHODS: We examine the expression and function of asHTF and full-length Tissue Factor ((FL)TF) in six human pancreatic cancer cells. Further, we transfected asHTF, (FL)TF, and control expression vectors into a non-expressing, human pancreatic cancer line (MiaPaCa-2). We studied the procoagulant activity of asHTF and (FL)TF and the effect on tumor growth in mice.
RESULTS: asHTF is expressed in 5 of 6 human pancreatic cancer cell lines, but not in normal human fibroblasts, nor the MiaPaCa-2 line. (FL)TF conferred procoagulant activity, but asHTF did not. Transfected cells were injected subcutaneously in athymic mice. Interestingly, compared with control transfection, (FL)TF expression was associated with reduced tumor growth (mean 7 mg vs 85 mg), while asHTF-expression was associated with enhanced tumor growth (mean 389 mg vs. 85 mg). asHTF expression resulted in increased mitotic index and microvascular density.
CONCLUSIONS: These data suggests that asHTF expression promotes tumor growth, and is associated with increased tumor cell proliferation and angiogenesis in vivo. Our results raise a new perspective on the understanding of the relationship between TF expression and cancer growth, by showing a dissociation of the procoagulant activity of (FL)TF and the cancer-promoting activity of asHTF.
Author List
Hobbs JE, Zakarija A, Cundiff DL, Doll JA, Hymen E, Cornwell M, Crawford SE, Liu N, Signaevsky M, Soff GAAuthor
Jennifer A. Doll PhD Assistant Professor in the Biomedical Sciences department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Alternative SplicingAnimals
Blood Coagulation
Cell Division
Cell Line, Tumor
Clone Cells
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Neovascularization, Pathologic
Pancreatic Neoplasms
Thromboplastin
Thrombosis
Transfection