Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.
Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.
复制标题
DOI：
10.1097/nen.0000000000000210
复制
发表时间：
2015-07
影响因子：
3.2
通讯作者：
Wakimoto H
中科院分区：
文献类型：
--
作者：
Nigim F;Cavanaugh J;Patel AP;Curry WT Jr;Esaki S;Kasper EM;Chi AS;Louis DN;Martuza RL;Rabkin SD;Wakimoto H
组织缺氧和坏死是胶质母细胞瘤(GBM)的病理生理和组织学特征。尽管缺氧诱导因子-1α(HIF-1α)在基底膜的恶性表型中起着关键作用，但由于缺乏一个合适的临床前模型来概括临床基底膜的复杂生物学特征，阻碍了开发以HIF-1α为靶点的药物。我们提出了一种新的基底膜模型MGG123，该模型是由复发性人基底膜建立的。干细胞样MGG123细胞原位异种移植可复制出致死性肿瘤，其特征为栅栏状坏死、多血管和干细胞标记物的强健表达。在异种移植和患者组织中，坏死性肿瘤细胞明显表达HIF-1α，并呈增殖状态。异种移植物含有分散的缺氧灶，与血管的距离始终为>；50μm，这表明肿瘤内氧合的异质性。低氧可促进MGG123细胞缺氧诱导因子-1α的表达，该作用可被地高辛或哇巴因抑制。在体内，地高辛治疗MGG123原位移植瘤可减少肿瘤内HIF-1mRNA表达、血管内皮生长因子α水平和CD34阳性血管，并延长携带侵袭性MGG123GBM的小鼠的存活时间。这种临床前肿瘤模型真实地概括了GBM相关的低氧微环境和茎干，是研究疾病生物学和开发低氧靶向药物的合适平台。
Tissue hypoxia and necrosis represent pathophysiological and histological hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently >50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness, and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.