We evaluated the significance of the host kallikrein-kinin system in
tumor angiogenesis and
tumor growth using two rodent models genetically deficient in a kallikrein-kinin system. Inoculation of Walker 256
carcinoma cells into the s.c. tissues of the back of normal Brown Norway Kitasato rats (BN-Ki rats) resulted in the rapid development of solid
tumors with marked angiogenesis. By contrast, in
kininogen-deficient Brown Norway Katholiek rats (BN-Ka rats), which cannot generate intrinsic
bradykinin (BK), the weights of the
tumors and the extent of angiogenesis were significantly less than those in BN-Ki rats. Daily administration of
B(2) receptor antagonists significantly reduced angiogenesis and
tumor weights in BN-Ki rats to levels similar to those in BN-Ka rats but did not do so in BN-Ka rats. Angiogenesis and
tumor growth were significantly suppressed in
B(2) receptor knockout mice bearing
sarcoma 180 compared with their wild-type counterparts. Immunoreactive
vascular endothelial growth factor (
VEGF) was localized in Walker
tumor stroma more extensively in BN-Ki rats than in BN-Ka rats, although immunoreactive
B(2) receptor also was detected in the stroma to the same extent in both types of rats. Cultured stromal fibroblasts isolated from BN-Ki rats and BN-Ka rats produced
VEGF in response to BK (10(-8)-10(-6) m), and this stimulatory effect of BK was abolished with a
B(2) receptor antagonist,
Hoe140 (10(-5) m). These results suggest that BK generated from
kininogens supplied from the host may facilitate
tumor-associated angiogenesis and
tumor growth by stimulating stromal
B(2) signaling to up-regulate
VEGF production mainly in fibroblasts.