BACKGROUND Circulating tumor cells (CTCs) represent a temporal "snapshot" of a patient's cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer. METHODS We used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice. RESULTS Staining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency. CONCLUSION PDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.

中文翻译：

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在三阴性乳腺癌患者源性原位异种移植模型中研究循环肿瘤细胞和远处转移。

背景技术循环肿瘤细胞（CTC）代表患者癌症的暂时“快照”以及疾病发展过程中发生的变化。有大量的文献研究乳腺癌患者，特别是那些患有转移性疾病的患者中的四氯化碳。同时，在人类癌症的临床前研究中，越来越多地使用基于患者的模型。然而，仍然有研究表明在患者源性乳腺癌模型中CTC脱落和转移形成的研究仍然有限。方法我们使用了三阴性乳腺癌（TNBC）患者产生的七个患者源性原位异种移植（PDOX）模型来研究CTC和远处转移。将来自七个模型中每个模型的PDOX组织的肿瘤片段植入57只NOD scidγ（NSG）小鼠中，并监测肿瘤的生长和体积。首先在与标记物无关的Vortex CTC分离平台上优化从小鼠血液中捕获人CTC，然后从37只带有PDOX肿瘤的小鼠中提取全血。结果染色和成像显示CTC的存在率为32/37（86％）。在不同的PDOX肿瘤模型之间以及携带相同的PDOX肿瘤的个别小鼠之间，CTC的总数各不相同。CTC是异质的，显示出细胞角蛋白（CK）阳性，波形蛋白（VIM）阳性以及CK / VIM混合表型。在肺（20 / 57，35％），肝（7 / 57，12％）和脑（1/57，少于2％）中检测到转移。七个不同的PDOX肿瘤模型显示出不同程度的转移潜力，其中包括一个TNBC PDOX肿瘤模型，尽管在血液中检测到5/5的CTC，该模型仍未产生任何可检测到的转移（0/8小鼠），提示来自该特定PDOX肿瘤模型的CTC可能代表转移性无效。结论脱落CTC并发生远处转移的PDOX肿瘤模型是研究TNBC的重要工具。