Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model.
BACKGROUND
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.


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.
Hobbs
Jennifer E
JE
The Division of Hematology/Oncology of the Feinberg School of Medicine at Northwestern University, Chicago, IL, USA. jennifer.hobbs@stjude.org
Zakarija
Anaadriana
A
Cundiff
Deborah L
DL
Doll
Jennifer A
JA
Hymen
Emily
E
Cornwell
Mona
M
Crawford
Susan E
SE
Liu
Na
N
Signaevsky
Maxim
M
Soff
Gerald A
GA
D017398:Alternative Splicing; D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D002455:Cell Division; D045744:Cell Line, Tumor; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013925:Thromboplastin / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics / Q000503:physiopathology; D014162:Transfection
D013925:Thromboplastin