Hypoxia Predicts Aggressive Growth and Spontaneous Metastasis Formation from Orthotopically Grown Primary Xenografts of Human Pancreatic Cancer
Hypoxia Predicts Aggressive Growth and Spontaneous Metastasis Formation from Orthotopically Grown Primary Xenografts of Human Pancreatic Cancer
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DOI：
10.1158/0008-5472.can-10-4049
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Hedley, David W.
中科院分区：
文献类型：
--
作者：
Chang, Qing;Jurisica, Igor;Hedley, David W.
实体瘤中的缺氧与治疗抵抗和转移潜力增加相关。虽然缺氧已被报道在胰腺癌患者，很少有直接证据表明，这有助于他们的整体预后不良。为了解决这个问题，我们研究了一系列原位生长的患者来源的异种移植物中缺氧和生物攻击之间的关系。从16名接受胰腺癌手术的患者中建立了早期传代异种移植物，并将其维持在免疫剥夺小鼠的胰腺中。使用2-硝基咪唑探针EF 5标记低分化细胞，并染色用于组织切片的免疫荧光显微镜检查或作为细胞悬浮液用于流式细胞术。溴脱氧尿苷（BrdUrd）摄取，微血管密度，裂解半胱天冬酶-3，和分化标志物E-钙粘蛋白，细胞角蛋白19和波形蛋白进行了分析与缺氧。原位植入物与原始手术样本的组织学非常相似。16例原发性异种移植物显示出广泛的生长速率和转移潜力，这让人想起了临床上看到的行为谱。EF 5标记，肿瘤生长速率和转移模式是高度一致的复制内，表明一个显着的传播（遗传或表观遗传）的组成部分。缺氧与肿瘤快速生长、BrdUrd摄取增加和自发转移形成高度相关。mRNA表达分析显示，在缺氧模型中参与细胞存活和增殖的基因表达增加。结果表明，缺氧是胰腺癌患者的一个主要不良预后因素，并支持引入技术来直接测量患者的缺氧，并制定针对缺氧的治疗方案。Cancer Res; 71（8）; 3110-20. (C)2011年AACR。
Hypoxia in solid tumors is associated with treatment resistance and increased metastatic potential. Although hypoxia has been reported in pancreatic cancer patients, there is little direct evidence that this contributes to their overall poor prognosis. To address this, we examined the associations between hypoxia and biological aggression in a series of patient-derived xenografts grown orthotopically. Early passage xenografts were established from 16 patients undergoing surgery for pancreatic cancer and maintained in the pancreas of immune-deprived mice. Hypoxic cells were labeled using the 2-nitroimidazole probe EF5 and stained for immunofluorescence microscopy of tissue sections or as cell suspensions for flow cytometry. Bromodeoxyuridine (BrdUrd) uptake, microvessel density, cleaved caspase-3, and the differentiation markers E-cadherin, cytokeratin 19, and vimentin were analyzed in relation to hypoxia. Orthotopic implants closely resembled the histology of the original surgical samples. The 16 primary xenografts showed a wide range in their growth rates and metastatic potential, reminiscent of the spectrum of behavior seen in the clinic. EF5 labeling, tumor growth rates, and metastatic patterns were highly consistent within replicates, indicating a significant transmissible (genetic or epigenetic) component. Hypoxia was highly correlated with rapid tumor growth, increased BrdUrd uptake, and with spontaneous metastasis formation. mRNA expression analysis showed increased expression of genes involved in cell survival and proliferation in the hypoxic models. The results suggest that hypoxia is a major adverse prognostic factor in pancreatic cancer patients and support the introduction of techniques to measure hypoxia directly in patients and the development of treatment protocols to target hypoxia. Cancer Res; 71(8); 3110-20. (C) 2011 AACR.