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Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth.

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.
AuthorsYasuhiro Ikeda, Izumi Hayashi, Emi Kamoshita, Akira Yamazaki, Hirahito Endo, Keiko Ishihara, Shohei Yamashina, Yoshiaki Tsutsumi, Hiroaki Matsubara, Masataka Majima
JournalCancer research (Cancer Res) Vol. 64 Issue 15 Pg. 5178-85 (Aug 01 2004) ISSN: 0008-5472 [Print] United States
PMID15289322 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Bradykinin B2 Receptor Antagonists
  • FR 173657
  • Kininogens
  • Quinolines
  • RNA, Messenger
  • Receptor, Bradykinin B2
  • Vascular Endothelial Growth Factor A
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacology)
  • Blood Vessels (drug effects, metabolism)
  • Bradykinin B2 Receptor Antagonists
  • Carcinoma 256, Walker (blood supply, pathology)
  • Fibroblasts (drug effects, metabolism)
  • Kallikrein-Kinin System
  • Kininogens (deficiency, genetics)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic (etiology)
  • Quinolines (administration & dosage, pharmacology)
  • RNA, Messenger (genetics, metabolism)
  • Rats
  • Rats, Inbred BN
  • Receptor, Bradykinin B2 (genetics, metabolism)
  • Sarcoma 180 (blood supply, pathology)
  • Signal Transduction
  • Stromal Cells (metabolism, pathology)
  • Vascular Endothelial Growth Factor A (genetics, metabolism)

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