Inhibition of VEGFR2 prevents DMBA-induced mammary tumor formation
Inhibition of VEGFR2 prevents DMBA-induced mammary tumor formation
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DOI：
10.1038/labinvest.3700128
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发表时间：
2004-08-01
影响因子：
5
通讯作者：
Warshawsky, D
中科院分区：
文献类型：
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作者：
Heffelfinger, SC;Yan, M;Warshawsky, D
人类和大鼠化学致癌模型系统中的浸润前乳腺病变相对于正常组织具有增加的微血管密度。这表明通过抑制血管生成来预防浸润性乳腺癌的可能性。血管内皮细胞生长因子（VEGF）是一种有效的血管生成生长因子，通常参与肿瘤诱导的血管生成。在这里，我们发现在大鼠 7,12-二甲基苯并[a]蒽 (DMBA) 模型中，VEGF 和 VEGFR2 表达随着组织学进展为侵袭性疾病而增加。其他 VEGF 受体 VEGFRI、神经毡蛋白 1 和神经毡蛋白 2 在整个进展过程中持续表达。为了检查 VEGF 信号传导是否与体外肿瘤诱导的内皮小管形成和体内肿瘤形成在功能上相关，我们使用了 VIEGFR2 抑制剂 ZD6474。 ZD6474 以剂量依赖性方式抑制由 DMBA 处理的大鼠分离的乳腺类器官或原位癌诱导的体外内皮细胞管状形成。对 DMBA 治疗的大鼠施用 ZD6474 可抑制非典型导管增生和原位癌的形成超过 95%（P
Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue. This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis. Vascular endothelial cell growth factor (VEGF) is a potent angiogenic growth factor, commonly involved in tumor-induced angiogenesis. Here, we show that both VEGF and VEGFR2 expression increase with histological progression to invasive disease in the rat 7,12-dimethylbenz[a]anthracene (DMBA) model. Other VEGF receptors, VEGFRI, neuropilin 1 and neuropilin 2, are constitutively expressed throughout progression. To examine whether VEGF signaling is functionally relevant to tumor-induced endothelial tubule formation in vitro and for tumor formation in vivo, we utilized the VIEGFR2 inhibitor, ZD6474. In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA-treated rats is inhibited by ZD6474, in a dose-dependent fashion. The administration of ZD6474 to DMBA-treated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95% (P