BACKGROUND Melanoma patients with metastatic growth in the meninges have poor prognosis and few treatment options. Although treatment with BRAF inhibitors or immune checkpoint inhibitors has provided promising results, most patients with advanced melanoma are resistant to these treatments and develop severe side effects. Novel treatment strategies are needed for patients with meningeal melanoma metastases, and the potential of antiangiogenic therapy was investigated in this preclinical study. METHODS Two GFP-transfected melanoma models (A-07 and D-12) differing substantially in VEGF-A expression were included in the study, and the anti-VEGF-A antibody bevacizumab was used as therapeutic agent. Meningeal metastases were initiated in BALB/c nu/nu mice by intracranial inoculation of melanoma cells, and bevacizumab treatment was given twice a week in i.p. doses of 10 mg/kg until the mice became moribund. Therapeutic effects were evaluated by determining tumor host survival time, assessing tumor growth and angiogenic activity by quantitative analyses of histological preparations, and measuring the expression of angiogenesis-related genes by quantitative PCR. RESULTS Meningeal A-07 melanomas showed higher expression of VEGF-A than meningeal D-12 melanomas, whereas the expression of ANGPT2 and IL8, two important angiogenesis drivers in melanoma, was much higher in D-12 than in A-07 tumors. Bevacizumab treatment inhibited tumor angiogenesis and prolonged host survival in mice with A-07 tumors but not in mice with D-12 tumors. Meningeal A-07 tumors in bevacizumab-treated mice compensated for the reduced VEGF-A activity by up-regulating a large number of angiogenesis-related genes, including ANGPT2 and its receptors TIE1 and TIE2. Melanoma cells migrated from meningeal tumors into the cerebrum, where they initiated metastatic growth by vessel co-option. In the A-07 model, the density of cerebral micrometastases was higher in bevacizumab-treated than in untreated mice, either because bevacizumab treatment increased mouse survival or induced increased tumor gene expression. CONCLUSIONS The development of antiangiogenic strategies for the treatment of meningeal melanoma metastases is a challenging task because the outcome of treatment will depend on the angiogenic signature of the tumor tissue, treatment-induced alterations of the angiogenic signature, and the treatment sensitivity of metastatic lesions in other intracranial sites.

中文翻译：

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贝伐单抗治疗脑膜黑色素瘤转移。

背景技术脑膜转移性黑色素瘤患者预后较差，治疗选择很少。尽管使用BRAF抑制剂或免疫检查点抑制剂进行治疗已提供了可喜的结果，但大多数晚期黑色素瘤患者对这些治疗均产生抗药性并产生严重的副作用。脑膜黑色素瘤转移患者需要新的治疗策略，并且在这项临床前研究中研究了抗血管生成治疗的潜力。方法本研究包括两种在GFP-A表达上有显着差异的GFP转染的黑色素瘤模型（A-07和D-12），并使用抗VEGF-A抗体贝伐单抗作为治疗药物。脑膜转移是通过颅内接种黑素瘤细胞在BALB / c nu / nu小鼠中引发的，每周两次以10 mg / kg的腹腔注射剂量给予贝伐单抗治疗，直至小鼠垂死。通过确定肿瘤宿主的生存时间，通过组织学制剂的定量分析评估肿瘤的生长和血管生成活性以及通过定量PCR测量血管生成相关基因的表达来评估治疗效果。结果脑膜A-07黑色素瘤比脑膜D-12黑色素瘤表达更高的VEGF-A，而在黑色素瘤中两个重要的血管生成驱动因子ANGPT2和IL8的表达则比A-07肿瘤高得多。贝伐单抗治疗在患有A-07肿瘤的小鼠中抑制了肿瘤的血管生成并延长了宿主的存活率，而在患有D-12肿瘤的小鼠中则没有。贝伐单抗治疗的小鼠中的脑膜A-07肿瘤通过上调包括ANGPT2及其受体TIE1和TIE2在内的大量血管生成相关基因来补偿VEGF-A活性降低。黑色素瘤细胞从脑膜肿瘤迁移到大脑，在那里它们通过血管选择共同启动转移性生长。在A-07模型中，贝伐单抗治疗后的脑微转移密度高于未治疗的小鼠，这是因为贝伐单抗治疗增加了小鼠的存活率或诱导了肿瘤基因表达的增加。结论开发治疗脑膜黑色素瘤转移的抗血管生成策略是一项艰巨的任务，因为治疗的结果将取决于肿瘤组织的血管生成特征，治疗诱导的血管生成特征改变，