Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy.
Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy.
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DOI：
10.18632/oncotarget.10212
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Yoon SS
中科院分区：
文献类型：
--
作者：
Yoon C;Chang KK;Lee JH;Tap WD;Hart CP;Simon MC;Yoon SS
用帕唑帕尼抑制血管内皮生长因子A（VEGF-A）是一种批准的肉瘤治疗方法，但可能导致代偿途径，如缺氧诱导因子1α（HIF-1α）上调。此外，癌症干细胞样细胞可以优先驻留在肿瘤的缺氧区域，并且对标准化疗具有抗性。在这项研究中，我们假设VEGF-A抑制、HIF-1α抑制和低氧激活化疗与evofosfamide联合应用将是一种有效的多模式策略。在一个基因工程和两个异种移植肉瘤小鼠模型中检查了多模式治疗。在所有三种模型中，多模式治疗在阻断肿瘤生长方面显示出比任何单药治疗或双模式治疗更大的疗效。即使在停止治疗后，用多模式治疗治疗的肿瘤仍保持相对休眠长达2个月。与第二好的双模式治疗相比，多模式治疗导致2.8-3.3倍的DNA损伤，1.5-2.7倍的总体细胞凋亡和2.3-3.6倍的内皮细胞特异性细胞凋亡。与对照组相比，多模式治疗还使微血管密度和HIF-1α活性分别降低了85-90%和79- 89%。与对照肿瘤相比，用多模式治疗的肉瘤具有95-96%的CD 133（+）癌症干细胞样细胞耗竭。在DNA损伤和凋亡方面，尤其是在缺氧条件下，生长为球状体以富集CD 133（+）癌症干细胞样细胞的肉瘤细胞比单层细胞对多模式治疗更敏感。因此，采用VEGF-A抑制、HIF-1α抑制和低氧激活化疗的肉瘤多模式治疗可通过抑制肿瘤血管和癌干细胞样细胞有效阻断肉瘤生长。
Vascular endothelial growth factor A (VEGF-A) inhibition with pazopanib is an approved therapy for sarcomas, but likely results in compensatory pathways such as upregulation of hypoxia inducible factor 1α (HIF-1α). In addition, cancer stem-like cells can preferentially reside in hypoxic regions of tumors and be resistant to standard chemotherapies. In this study, we hypothesized that the combination of VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy with evofosfamide would be an effective multimodal strategy. Multimodal therapy was examined in one genetically engineered and two xenograft mouse models of sarcoma. In all three models, multimodal therapy showed greater efficacy than any single agent therapy or bimodality therapy in blocking tumor growth. Even after cessation of therapy, tumors treated with multimodal therapy remained relatively dormant for up to 2 months. Compared to the next best bimodality therapy, multimodal therapy caused 2.8-3.3 fold more DNA damage, 1.5-2.7 fold more overall apoptosis, and 2.3-3.6 fold more endothelial cell-specific apoptosis. Multimodal therapy also decreased microvessel density and HIF-1α activity by 85-90% and 79-89%, respectively, compared to controls. Sarcomas treated with multimodal therapy had 95-96% depletion of CD133(+) cancer stem-like ells compared to control tumors. Sarcoma cells grown as spheroids to enrich for CD133(+) cancer stem-like cells were more sensitive than monolayer cells to multimodal therapy in terms of DNA damage and apoptosis, especially under hypoxic conditions. Thus multimodal therapy of sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy effectively blocks sarcoma growth through inhibition of tumor vasculature and cancer stem-like cells.
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