High incidence of tumors in diabetic thrombin activatable fibrinolysis inhibitor and apolipoprotein E double-deficient mice.
BACKGROUND
Activation of the complement system has been implicated in tumor growth. The antifibrinolytic protein, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), can modulate the activation of the complement system by inactivating the anaphylatoxins C3a and C5a. The apolipoprotein-E (ApoE) genotype has been associated with carcinogenesis.


OBJECTIVE
The aim of this study was to evaluate whether TAFIa can affect the development of cancer in the ApoE-deficient mouse model.


METHODS
TAFI and ApoE double-knockout mice were generated. A group of mice was treated with the diabetogenic and carcinogenic compound streptozotocin (stz). Mice treated with saline, single knockout mice and wild-type (wt) mice served as controls.


RESULTS
Six months after treatment with stz, mice were sacrificed. Hepatic tumors were found in male double-knockout mice treated with stz but none was found in control animals that were not treated with stz or in single knockout of ApoE or wt animals. There was no significant difference in coagulation system activation between the groups of mice. The plasma concentrations of C5a, factor D and transforming growth factor-β1 were increased in TAFI/ApoE double-deficient mice treated with stz compared with the mice of the same genotype treated with saline.


CONCLUSIONS
Apo-E deficiency alone was not associated with tumors but the lack of TAFI appears to make the mice permissive for tumor formation in ApoE mice.
Beppu
T
T
Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Gil-Bernabe
P
P
Boveda-Ruiz
D
D
D'Alessandro-Gabazza
C
C
Matsuda
Y
Y
Toda
M
M
Miyake
Y
Y
Shiraki
K
K
Murata
M
M
Murata
T
T
Yano
Y
Y
Morser
J
J
Gabazza
E C
EC
Takei
Y
Y
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D025901:Carboxypeptidase B2 / Q000235:genetics*; D003167:Complement Activation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005342:Fibrinolysis; D005838:Genotype; D006720:Homozygote; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics*; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors
D001057:Apolipoproteins E; D013311:Streptozocin; D025901:Carboxypeptidase B2