Identifying biomarkers of breast cancer micrometastatic disease in bone marrow using a patient-derived xenograft mouse model.
Identifying biomarkers of breast cancer micrometastatic disease in bone marrow using a patient-derived xenograft mouse model.
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DOI：
10.1186/s13058-017-0927-1
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发表时间：
2018-01-02
期刊：
影响因子：
--
通讯作者：
Aft R
中科院分区：
文献类型：
--
作者：
Pillai SG;Li S;Siddappa CM;Ellis MJ;Watson MA;Aft R
在乳腺癌患者的骨髓（BM）中发现弥散性肿瘤细胞（dtc）预示着预后不良，并且被认为是转移过程中的中介。为了评估识别这些细胞可能的预后和预测性生物标志物的小鼠模型的临床相关性，我们采用患者来源的异种移植物（PDX）进行人类dtc的繁殖和分子分析。先前开发的来自5名乳腺癌患者的小鼠异种移植物通过植入NOD/SCID小鼠乳腺脂肪垫进一步传代。在早期的连续传代中从长骨中收集BM，并通过qRT-PCR分析人类特异性基因表达，作为检测dtc的替代生物标志物。基于微阵列的基因表达分析比较了原发异种移植物、实体转移和BM dtc群体之间的表达谱。然后将基因表达的差异模式与先前从乳腺癌患者和健康志愿者的原发人骨髓抽吸中生成的微阵列数据进行比较。SNAI1、GSC、FOXC2、KRT19和STAM2的人类特异性基因表达可能起源于dtc，在所有发生转移性肿瘤的异种移植小鼠的骨髓中检测到。在那些没有远处转移证据的异种移植物系和未移植的对照小鼠的骨髓中检测不到人类特异性基因的表达。BM dtc与原发肿瘤的基因表达比较分析发现了与上皮-间质转化、侵袭性临床表型和转移性疾病发展相关的多个基因转录本。16种PDX乳腺癌相关基因在健康志愿者的乳腺癌与远处转移性乳腺癌患者的乳腺癌中的表达也有统计学上的显著差异。独特的和可重复的差异基因表达模式可以确定，可能起源于小鼠PDX系的BM dtc。其中一些已鉴定的基因也在早期转移的乳腺癌患者的BM中检测到，这表明它们可能是临床相关的生物标志物。PDX模型也可能为分析和靶向这些转移媒介提供临床相关的系统。本文的在线版本（doi:10.1186/s13058-017-0927-1）包含补充材料，可供授权用户使用。
Disseminated tumor cells (DTCs) found in the bone marrow (BM) of patients with breast cancer portend a poor prognosis and are thought to be intermediaries in the metastatic process. To assess the clinical relevance of a mouse model for identifying possible prognostic and predictive biomarkers of these cells, we have employed patient-derived xenografts (PDX) for propagating and molecularly profiling human DTCs. Previously developed mouse xenografts from five breast cancer patients were further passaged by implantation into NOD/SCID mouse mammary fat pads. BM was collected from long bones at early, serial passages and analyzed for human-specific gene expression by qRT-PCR as a surrogate biomarker for the detection of DTCs. Microarray-based gene expression analyses were performed to compare expression profiles between primary xenografts, solid metastasis, and populations of BM DTCs. Differential patterns of gene expression were then compared to previously generated microarray data from primary human BM aspirates from patients with breast cancer and healthy volunteers. Human-specific gene expression of SNAI1, GSC, FOXC2, KRT19, and STAM2, presumably originating from DTCs, was detected in the BM of all xenograft mice that also developed metastatic tumors. Human-specific gene expression was undetectable in the BM of those xenograft lines with no evidence of distant metastases and in non-transplanted control mice. Comparative gene expression analysis of BM DTCs versus the primary tumor of one mouse line identified multiple gene transcripts associated with epithelial-mesenchymal transition, aggressive clinical phenotype, and metastatic disease development. Sixteen of the PDX BM associated genes also demonstrated a statistically significant difference in expression in the BM of healthy volunteers versus the BM of breast cancer patients with distant metastatic disease. Unique and reproducible patterns of differential gene expression can be identified that presumably originate from BM DTCs in mouse PDX lines. Several of these identified genes are also detected in the BM of patients with breast cancer who develop early metastases, which suggests that they may be clinically relevant biomarkers. The PDX model may also provide a clinically relevant system for analyzing and targeting these intermediaries of metastases. The online version of this article (doi:10.1186/s13058-017-0927-1) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.6
作者：
Huang KL;Li S;Mertins P;Cao S;Gunawardena HP;Ruggles KV;Mani DR;Clauser KR;Tanioka M;Usary J;Kavuri SM;Xie L;Yoon C;Qiao JW;Wrobel J;Wyczalkowski MA;Erdmann-Gilmore P;Snider JE;Hoog J;Singh P;Niu B;Guo Z;Sun SQ;Sanati S;Kawaler E;Wang X;Scott A;Ye K;McLellan MD;Wendl MC;Malovannaya A;Held JM;Gillette MA;Fenyö D;Kinsinger CR;Mesri M;Rodriguez H;Davies SR;Perou CM;Ma C;Reid Townsend R;Chen X;Carr SA;Ellis MJ;Ding L
通讯作者：
Ding L
影响因子：
78.5
作者：
Klein, Christoph A.
通讯作者：
Klein, Christoph A.
DOI：
10.1073/pnas.0401064101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Kuperwasser, C;Chavarria, T;Weinberg, RA
通讯作者：
Weinberg, RA
影响因子：
11.2
作者：
Lunter, PC;van Kilsdonk, JWJ;Swart, GWM
通讯作者：
Swart, GWM