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Host Stromal Bradykinin B₂ Receptor Signaling Facilitates Tumor-Associated Angiogenesis and Tumor Growth

¹ Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan; Departments of ² Obstetrics and Gynecology, ³ Pharmacology, and ⁴ Anatomy, Kitasato University School of Medicine, Kanagawa, Japan; and ⁵ Department of Medicine II, Kansai Medical University, Osaka, Japan

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 B₂ 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 B₂ 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 B₂ 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 B₂ 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 B₂ signaling to up-regulate VEGF production mainly in fibroblasts.

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