Morton J J, Bird G, Keysar S B, Astling D P, Lyons T R, Anderson R T, Glogowska M J, Estes P, Eagles J R, Le P N, Gan G, McGettigan B, Fernandez P, Padilla-Just N, Varella-Garcia M, Song J I, Bowles D W, Schedin P, Tan A-C, Roop D R, Wang X-J, Refaeli Y, Jimeno A
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
Department of Dermatology, University of Colorado School of Medicine.
Oncogene. 2016 Jan 21;35(3):290-300. doi: 10.1038/onc.2015.94. Epub 2015 Apr 20.
The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.
癌细胞系的局限性促使了直接源自患者的异种移植模型的发展。然而，植入的人类癌细胞与募集的小鼠基质细胞和免疫细胞之间的相互作用改变了肿瘤微环境，并限制了这些模型的价值。为了克服这些限制，我们开发了一种技术来扩增人类造血干细胞和祖细胞（HSPC），并用它们来重建NOD/SCID/IL2rg(-/-)（NSG）小鼠经辐射耗尽的骨髓，然后在该小鼠上移植患者的肿瘤（XactMice）。人类HSPC产生归巢到肿瘤中的免疫细胞，并有助于复制其天然微环境。尽管之前在裸鼠上传代，但XactMice肿瘤中上皮、基质和免疫基因的表达与患者肿瘤的表达比与在未人源化小鼠中生长的肿瘤的表达更接近——HSPC后代和肿瘤细胞表达的人类细胞因子部分促进了这一效应。XactMice中产生的人类免疫和基质细胞有助于重现植入异种移植的微环境，逆转在未人源化小鼠上传代后出现的初始基因漂移，并提供更准确的肿瘤模型来指导患者治疗。
