Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth
Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth
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DOI：
10.1158/0008-5472.can-03-3589
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Majima, M
中科院分区：
文献类型：
--
作者：
Ikeda, Y;Hayashi, I;Majima, M
我们使用激肽释放酶-激肽系统遗传缺陷的两种啮齿动物模型评估了宿主激肽释放酶-激肽系统在肿瘤血管生成和肿瘤生长中的重要性。将 Walker 256 癌细胞接种到皮下正常棕色挪威Kitasato大鼠（BN-Ki大鼠）背部组织导致实体瘤快速发展，并伴有明显的血管生成。相比之下，缺乏激肽原的布朗挪威Katholiek大鼠（BN-Ka大鼠）无法产生内在的缓激肽（BK），其肿瘤重量和血管生成程度均显着低于BN-Ki大鼠。每日施用 B-2 受体拮抗剂可显着减少 BN-Ki 大鼠的血管生成和肿瘤重量，使其达到与 BN-Ka 大鼠相似的水平，但在 BN-Ka 大鼠中却没有这种效果。与野生型小鼠相比，携带肉瘤 180 的 B-2 受体敲除小鼠的血管生成和肿瘤生长受到显着抑制。 BN-Ki 大鼠的免疫反应性血管内皮生长因子 (VEGF) 比 BN-Ka 大鼠更广泛地定位于 Walker 肿瘤基质中，尽管在两种类型的大鼠的基质中也检测到相同程度的免疫反应性 B-2 受体。从 BN-Ki 大鼠和 BN-Ka 大鼠中分离的培养基质成纤维细胞响应 BK (10(-8)-10(-6) M) 产生 VEGF，并且 BK 的这种刺激作用被 B-2 受体拮抗剂 Hoe140 (10(-5) M) 消除。这些结果表明，由宿主提供的激肽原产生的 BK 可能通过刺激基质 B-2 信号传导上调主要在成纤维细胞中的 VEGF 产生来促进肿瘤相关的血管生成和肿瘤生长。
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.