Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth.
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.
Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Kanagawa 228-8555, Japan.
Yasuhiro
Y
Ikeda
Izumi
I
Hayashi
Emi
E
Kamoshita
Akira
A
Yamazaki
Hirahito
H
Endo
Keiko
K
Ishihara
Shohei
S
Yamashina
Yoshiaki
Y
Tsutsumi
Hiroaki
H
Matsubara
Masataka
M
Majima
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D065094:Bradykinin B2 Receptor Antagonists; D002279:Carcinoma 256, Walker / Q000098:blood supply* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016234:Kallikrein-Kinin System; D007704:Kininogens / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D012510:Sarcoma 180 / Q000098:blood supply* / Q000473:pathology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065094:Bradykinin B2 Receptor Antagonists; C105311:FR 173657; D007704:Kininogens; D011804:Quinolines; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D042461:Vascular Endothelial Growth Factor A