1. Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth.
- Author
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Ikeda Y, Hayashi I, Kamoshita E, Yamazaki A, Endo H, Ishihara K, Yamashina S, Tsutsumi Y, Matsubara H, and Majima M
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Blood Vessels drug effects, Blood Vessels metabolism, Bradykinin B2 Receptor Antagonists, Carcinoma 256, Walker pathology, Fibroblasts drug effects, Fibroblasts metabolism, Kallikrein-Kinin System, Kininogens genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Quinolines administration & dosage, Quinolines pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Inbred BN, Receptor, Bradykinin B2 genetics, Sarcoma 180 pathology, Signal Transduction, Stromal Cells metabolism, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Carcinoma 256, Walker blood supply, Kininogens deficiency, Neovascularization, Pathologic etiology, Receptor, Bradykinin B2 metabolism, Sarcoma 180 blood supply, Stromal Cells pathology
- Abstract
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.
- Published
- 2004
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