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Abstract：
Xenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancer in vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell line in vivo to reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a \"difficult to xenograft\" PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.
摘要：
将人类癌症组织异种移植到小鼠体内以测试新的癌症治疗方法对于理解和治疗这种疾病至关重要。然而,只有少数近交系小鼠被用来研究癌症，以及主要是一种菌株的衍生物，主要是NOD/ShiLtJ，用于治疗效果研究。正如已经证明的那样，当人类癌细胞系或患者来源的组织（PDX）被异种移植到小鼠体内时，例如,肿瘤细胞是人的,但包含肿瘤(基质)的支持细胞来自小鼠。因此,异种移植组织的研究结果受宿主菌株的影响。我们以前发表过，当相同的肿瘤细胞异种移植到不同的小鼠品系中时，肿瘤生长的模式，肿瘤的组织学，浸润肿瘤的免疫细胞数量，循环细胞因子的类型因菌株而异。因此,为了更好地理解癌症在体内的行为，必须异种移植多个小鼠品系。在这里，我们描述并报告了一系列方法，我们用来揭示相同癌细胞系时表达的基因和蛋白质，MDA-MB-231在不同的宿主中异种移植。首先,使用蛋白质组学分析，我们展示了如何在体内使用相同的细胞系来揭示肿瘤细胞中有助于其适应宿主的蛋白质变化。然后，我们展示了不同的宿主对同一细胞系的分子反应。我们还发现，使用多种菌株可以揭示比传统上用于“难以异种移植”PDX的宿主更合适的宿主。此外,利用复杂的性状遗传学，我们说明了发现支持肿瘤生长的宿主等位基因的可行方法。最后,我们证明了多样性远交小鼠，小鼠品系遗传多样性模型的缩影，可以使用2-脱氧-D-葡萄糖处理与人细胞系或PDX异种移植。
