The impact of initial tumor microenvironment on imaging phenotype.
The impact of initial tumor microenvironment on imaging phenotype.
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DOI：
10.1016/j.ctarc.2021.100315
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发表时间：
2021
影响因子：
--
通讯作者：
Ewing JR
中科院分区：
文献类型：
--
作者：
Nagaraja TN;deCarvalho AC;Brown SL;Griffith B;Farmer K;Irtenkauf S;Hasselbach L;Mukherjee A;Bartlett S;Valadie OG;Cabral G;Knight RA;Lee IY;Divine GW;Ewing JR
人类癌症模型要想发挥作用，就必须高度逼真地复制人类疾病。我们在这项研究中的重点是大鼠异种移植脑肿瘤作为人类嵌入式脑肿瘤的模型。当人类细胞在啮齿动物中生长时，人类中这种肿瘤的一个区别性特征，即成像上的对比度增强，通常不存在，尽管异种移植物具有与原始肿瘤标本几乎相同的DNA特征。虽然对比度增强是均匀明显的所有人类肿瘤的异种移植物的细胞来源，我们表明，长期对比度增强模型肿瘤可以有条件地确定在细胞植入时的肿瘤微环境。我们证明了这一现象的两个患者来源的原位异种移植（PDOX）模型之一，使用癌症干细胞样细胞（CSC）富集的神经球从人类肿瘤切除标本，移植到免疫功能低下的大鼠组中的存在或不存在的胶原蛋白/纤维蛋白支架基质，基质胶。采用动态对比增强磁共振成像（DCE-MRI）对大鼠进行成像，并对其脑进行组织病理学检查。从植入有和没有基质胶的CSC生长的PDOX肿瘤标本的靶向蛋白质组学显示，虽然大多数蛋白质和翻译后修饰的水平在对比度增强和非增强肿瘤之间是相当的，但Fox 038的磷酸化显示出差异表达。结果表明，关键蛋白质决定对比度增强，并提出了一个更好的人类胶质瘤动物模型的发展道路。未来的工作需要充分阐明对比度增强的分子决定因素。
Models of human cancer, to be useful, must replicate human disease with high fidelity. Our focus in this study is rat xenograft brain tumors as a model of human embedded cerebral tumors. A distinguishing signature of such tumors in humans, that of contrast-enhancement on imaging, is often not present when the human cells grow in rodents, despite the xenografts having nearly identical DNA signatures to the original tumor specimen. Although contrast enhancement was uniformly evident in all the human tumors from which the xenografts’ cells were derived, we show that long-term contrast enhancement in the model tumors may be determined conditionally by the tumor microenvironment at the time of cell implantation. We demonstrate this phenomenon in one of two patient-derived orthotopic xenograft (PDOX) models using cancer stem-like cell (CSC)-enriched neurospheres from human tumor resection specimens, transplanted to groups of immune-compromised rats in the presence or absence of a collagen/fibrin scaffolding matrix, Matrigel. The rats were imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and their brains were examined by histopathology. Targeted proteomics of the PDOX tumor specimens grown from CSC implanted with and without Matrigel showed that while the levels of the majority of proteins and post-translational modifications were comparable between contrast-enhancing and non-enhancing tumors, phosphorylation of Fox038 showed a differential expression. The results suggest key proteins determine contrast enhancement and suggest a path toward the development of better animal models of human glioma. Future work is needed to elucidate fully the molecular determinants of contrast-enhancement.