Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth
Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth
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DOI：
10.1093/carcin/bgh324
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发表时间：
2005-02-01
期刊：
影响因子：
4.7
通讯作者：
Majima, M
中科院分区：
文献类型：
--
作者：
Fujita, M;Hayashi, I;Majima, M
血管紧张素II是一种多功能生物活性肽，最近的报道表明血管紧张素II是一种促血管生成生长因子。一项回顾性队列研究显示，血管紧张素转换酶抑制剂可降低癌症风险，但其确切机制尚不清楚。我们假设内源性血管紧张素II在肿瘤相关血管生成中起着至关重要的作用。在血管内皮生长因子（VEGF）诱导下，植入野生型小鼠皮下组织的肿瘤在肿瘤基质中发生了强烈的血管新生。肿瘤基质中表达AT1a受体（AT1a- r），但不表达AT1b受体或AT2受体，并且全身给予AT1-R拮抗剂可降低肿瘤基质中肿瘤相关血管生成和VEGF的表达。血管紧张素II通过蛋白激酶C、AP-1、NF-kappaB等途径在成纤维细胞（肿瘤基质的主要细胞成分）中上调VEGF的表达。在目前的模型中，VEGF是肿瘤相关血管生成的主要决定因素，因为血管生成被VEGF中和抗体或VEGF受体激酶抑制剂显著减少。与野生型相比，AT1a-R缺失小鼠的肿瘤相关血管生成减少，基质中VEGF表达减少，并且AT1a-R缺失小鼠的这种减少不受AT1-R拮抗剂的抑制。这表明AT1a-R信号诱导宿主间质VEGF是肿瘤相关血管生成和肿瘤生长的关键调节因子。AT1a-R信号阻断可能是一种新的有效的癌症治疗策略。
Angiotensin II is a multi-functional bioactive peptide and recent reports have suggested that angiotensin II is a proangiogenic growth factor. A retrospective cohort study revealed that angiotensin converting enzyme inhibitors decreased cancer risk, however, the precise mechanism is unknown. We hypothesized that endogenous angiotensin II plays a crucial role in tumor-associated angiogenesis. Tumors implanted in the subcutaneous tissue of wild-type mice developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b receptor or AT2 receptor was expressed in tumor stroma and systemic administration of an AT1-R antagonist reduced tumor-associated angiogenesis and VEGF expression in tumor stroma. Angiotensin II up-regulates VEGF expression through the pathway including protein kinase C, AP-1 and NF-kappaB in fibroblasts, the major cellular component of tumor stroma. VEGF is a major determinant of tumor-associated angiogenesis in the present model, since angiogenesis was markedly reduced by either a VEGF neutralizing antibody or a VEGF receptor kinase inhibitor. Compared with the wild-type, tumor-associated angiogenesis was reduced in AT1a-R null mice, with reduced expression of VEGF in the stroma, and this reduction in AT1a-R null mice was not inhibited by an AT1-R antagonist. These suggest that host stromal VEGF induction by AT1a-R signaling is a key regulator of tumor-associated angiogenesis and tumor growth. AT1a-R signaling blockade may be a novel and effective therapeutic strategy against cancers.