Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option
Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option
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DOI：
10.1158/1078-0432.ccr-04-0823
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
de Waal, R
中科院分区：
文献类型：
--
作者：
Leenders, WPJ;Küsters, B;de Waal, R
目的：在脑中，肿瘤可以通过与致密的预先存在的毛细血管床共存而在不诱导血管生成的情况下生长。本研究的目的是探讨这种现象如何影响antiangiogenictherapy.Experimental设计的结果：小鼠携带脑转移的人，高度血管生成的黑色素瘤细胞系Mel 57-VEGF-A要么或不处理与不同剂量的ZD 6474，血管内皮生长因子（VEGF）受体2酪氨酸激酶抑制剂与额外的活性对表皮生长因子受体。使用对比增强磁共振成像（CE-MRI）和（免疫）形态学analysis.Results：安慰剂治疗的Mel 57-VEGF-A脑转移瘤引起血管生成反应，并突出显示在CE-MRI的治疗效果进行了评价。ZD 6474（100 mg/kg）给药后，CE-MRI在预防或治疗方案中均未检出肿瘤。然而，（免疫）组织学分析显示存在大量的，小的非血管生成病变。治疗与25毫克/公斤ZD 6474也导致了有效的封锁血管形成，但它没有完全抑制血管渗漏，从而仍然允许可视化CE-MRI scannes.Conclusions：我们的数据表明，虽然血管生成可以有效地阻止ZD 6474，在血管密集的器官，这可能会导致持续的肿瘤进展，通过合作选择，而不是在肿瘤休眠。重要的是，阻断VEGF-A可能导致CE-MRI扫描中无法检测到肿瘤，从而导致磁共振成像随访期间关于治疗疗效的错误结论。在不存在新血管形成的情况下，在较低ZD 6474剂量下维持VEGF-A诱导的血管渗漏可用于改善血管生成和化疗化合物联合治疗方案中化疗药物的递送。
Purpose: In the brain, tumors may grow without inducing angiogenesis, via co-option of the dense pre-existent capillary bed. The purpose of this study was to investigate how this phenomenon influences the outcome of antiangiogenic therapy.Experimental Design: Mice carrying brain metastases of the human, highly angiogenic melanoma cell line Mel57-VEGF-A were either or not treated with different dosages of ZD6474, a vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase inhibitor with additional activity against epidermal groeth factor receptor. Effect of treatment was evaluated using contrast-enhanced magnetic resonances imaging (CE-MRI) and (immuno)morphologic analysis.Results: Placebo-treated Mel57-VEGF-A brain metastases evoked an angiogenic response and were highlighted in CE-MRI. After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens. However, (immuno)histologic analysis revealed the presence of numerous, small nonangiogenic lesions. Treatment with 25 mg/kg ZD6474 also resulted in efficient blockade of vessel formation, but it did not fully inhibit vascular leakage, thereby still allowing visualization in CE-MRI scans.Conclusions: Our data show that, although angiogeniesis can be effectively blocked by ZD6474, in vessel-dense organs this may result in sustained tumor progression via co-option, rather than in tumor dormancy. Importantly, blocking VEGF-A may result in undetectability of tumors in CE-MRI scans, leading to erraneous conclusions about therapeutic efficacy during magnetic resonance imaging follow-up. The maintenance of VEGF-A- induced vessel leakage in the absence of neovascularization at lower ZD6474 doses may be exploited to improve delivery of chemotherapeutic agents in combined treatment regimens of angiogenic and chemotherapeutic compounds.