A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models.
A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models.
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具有表型稳定，生物学和种族多样的，患者衍生的人类乳腺癌异种移植模型的可再生组织资源。
DOI：
10.1158/0008-5472.can-12-4081
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发表时间：
2013-08-01
期刊：
影响因子：
11.2
通讯作者：
Lewis MT
中科院分区：
文献类型：
--
作者：
Zhang X;Claerhout S;Prat A;Dobrolecki LE;Petrovic I;Lai Q;Landis MD;Wiechmann L;Schiff R;Giuliano M;Wong H;Fuqua SW;Contreras A;Gutierrez C;Huang J;Mao S;Pavlick AC;Froehlich AM;Wu MF;Tsimelzon A;Hilsenbeck SG;Chen ES;Zuloaga P;Shaw CA;Rimawi MF;Perou CM;Mills GB;Chang JC;Lewis MT
由于难以获得和研究原代人乳腺组织，以及缺乏准确反映患者肿瘤生物学的体内临床前模型，乳腺癌研究受到了阻碍。为了克服这些局限性，我们在一系列移植条件下，在SCID/Beige和NOD/SCID/ il2 γ-受体缺失（NSG）小鼠的无上皮乳腺脂肪垫中培养了一组人乳腺肿瘤。两种模型均以相当高的比率（分别为~21%和~19%）获得稳定的移植异种移植物。在测试的条件下，在低剂量雌二醇颗粒存在的情况下，异种移植物的接受率最高。总的来说，建立了32个稳定移植的异种移植物系，代表25个独特的患者。大多数产生异种移植物的肿瘤为“三阴性”（ER-PR-HER2+） （n=19）。然而，我们从三个ER-PR-HER2+肿瘤、一个ER+PR-HER2 -、一个ER+PR+HER2 -和一个“三阳性”（ER+PR+HER2+）肿瘤中建立了细胞系。连续传代的异种移植物显示出与原发肿瘤的生物学一致性，在组织学、转录组学、蛋白质组学和基因组水平上，在多代移植中表现出表型稳定，并显示出与临床观察相当的治疗反应。12例患者的异种移植物，包括2例ER+细胞系，显示转移到小鼠肺。因此，这些模型作为一种可再生的、质量控制的组织资源，用于研究治疗反应和转移的临床前研究。
Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2−, one ER+PR+HER2− and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis.