A novel model for evaluating therapies targeting human tumor vasculature and human cancer stem-like cells.
A novel model for evaluating therapies targeting human tumor vasculature and human cancer stem-like cells.
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DOI：
10.1158/0008-5472.can-12-2845
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发表时间：
2013-06-15
期刊：
影响因子：
11.2
通讯作者：
Buckanovich RJ
中科院分区：
文献类型：
--
作者：
Burgos-Ojeda D;McLean K;Bai S;Pulaski H;Gong Y;Silva I;Skorecki K;Tzukerman M;Buckanovich RJ
人类肿瘤血管表达肿瘤血管标记物（tumor vascular markers, TVMs），即正常血管中不表达的蛋白质。针对tvm的抗体可以作为有效的治疗药物。不幸的是，由于缺乏证实人类TVM表达的体内模型，测试抗人类TVM疗法的临床前体内研究很难进行。因此，我们评估了TVM在人类胚胎干细胞衍生畸胎瘤（hESCT）肿瘤模型中的表达，该模型先前显示有人类血管。我们现在报道，在肿瘤细胞存在的情况下，hESCT肿瘤血管表达人类tvm。小鼠胚胎成纤维细胞和人肿瘤内皮细胞的加入显著增加了人肿瘤血管的数量。TVM的诱导主要是肿瘤类型特异性的，卵巢癌细胞主要诱导卵巢TVM，而乳腺癌细胞诱导乳腺癌特异性TVM。我们证明了该模型用于测试抗人类特异性TVM免疫疗法的实用性；抗人Thy-1 TVM免疫疗法导致中心肿瘤坏死，并使人肿瘤血管密度降低三倍。最后，我们测试了具有人肿瘤血管生态位的hESCT模型提高原发人卵巢癌干细胞（CSC）植入率的能力。来自患者（n=6）的ALDH+ CSC在4-12周内移植到hESCT，而没有移植到侧翼。ALDH-卵巢癌细胞在hESCT或侧腹未见移植（n=3）。因此，该模型是测试抗人TVM治疗和评估体内人CSC肿瘤生物学的有用工具。
Human tumor vessels express tumor vascular markers (TVMs), proteins that are not expressed in normal blood vessels. Antibodies targeting TVMs could act as potent therapeutics. Unfortunately, preclinical in vivo studies testing anti-human TVM therapies have been difficult to perform due to a lack of in vivo models with confirmed expression of human TVMs. We therefore evaluated TVM expression in a human embryonic stem cell derived teratoma (hESCT) tumor model previously shown to have human vessels. We now report that, in the presence of tumor cells, hESCT tumor vessels express human TVMs. The addition of mouse embryonic fibroblasts and human tumor endothelial cells significantly increases the number of human tumor vessels. TVM induction is mostly tumor type specific with ovarian cancer cells inducing primarily ovarian TVMs while breast cancer cells induce breast cancer specific TVMs. We demonstrate the utility of this model to test an anti-human specific TVM immunotherapeutics; anti-human Thy-1 TVM immunotherapy results in central tumor necrosis and a three-fold reduction in human tumor vascular density. Finally, we tested the ability of the hESCT model, with human tumor vascular niche, to enhance the engraftment rate of primary human ovarian cancer stem-like cells (CSC). ALDH+ CSC from patients (n=6) engrafted in hESCT within 4–12 weeks whereas none engrafted in the flank. ALDH- ovarian cancer cells showed no engraftment in the hESCT or flank (n=3). Thus this model represents a useful tool to test anti-human TVM therapy and evaluate in vivo human CSC tumor biology.