Gene expression profiling of 49 human tumor xenografts from in vitro culture through multiple in vivo passages - strategies for data mining in support of therapeutic studies

BMC Genomics

Jerry Collins⁷  Howard Stotler¹  Michael E Mullendore¹  Angelena Millione¹  Mark W Kunkel³  David J Kimmel¹  Gurmeet Kaur⁴  Susan L Holbeck³  Elizabeth J Hager⁵  Kelly M Dougherty¹  Raymond Divelbiss¹  Suzanne D Borgel¹  Carrie A Bonomi¹  Benjamin C Orsburn²  Dianne L Newton¹  Sergio Y Alcoser⁵  Luke H Stockwin¹  Melinda G Hollingshead⁶ 

[1] Biological Testing Branch, Developmental Therapeutics Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;Thermo Fisher, 134 Yorkshire Boulevard, Indianapolis, IN, USA;Information Technology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD 20892, USA;Molecular Pharmacology Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA;Biological Testing Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA;Biological Testing Branch, National Cancer Institute at Frederick, 1050 Boyles Street, Building 1043, Room 11, Frederick, MD 21702, USA;Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD 20892, USA

关键词: in vitro to in vivo transition;    Transcriptomic expression;    Transcriptomic stability;    NCI-60 cell line screen;    cDNA microarray;    Affymetrix HG-U133 Plus 2.0 array;    Xenograft models;   

Others  :  1217204
DOI  :  10.1186/1471-2164-15-393

 received in 2013-11-18, accepted in 2014-05-09,  发布年份 2014

【 摘 要 】

Background

Development of cancer therapeutics partially depends upon selection of appropriate animal models. Therefore, improvements to model selection are beneficial.

Results

Forty-nine human tumor xenografts at in vivo passages 1, 4 and 10 were subjected to cDNA microarray analysis yielding a dataset of 823 Affymetrix HG-U133 Plus 2.0 arrays. To illustrate mining strategies supporting therapeutic studies, transcript expression was determined: 1) relative to other models, 2) with successive in vivo passage, and 3) during the in vitro to in vivo transition. Ranking models according to relative transcript expression in vivo has the potential to improve initial model selection. For example, combining p53 tumor expression data with mutational status could guide selection of tumors for therapeutic studies of agents where p53 status purportedly affects efficacy (e.g., MK-1775). The utility of monitoring changes in gene expression with extended in vivo tumor passages was illustrated by focused studies of drug resistance mediators and receptor tyrosine kinases. Noteworthy observations included a significant decline in HCT-15 colon xenograft ABCB1 transporter expression and increased expression of the kinase KIT in A549 with serial passage. These trends predict sensitivity to agents such as paclitaxel (ABCB1 substrate) and imatinib (c-KIT inhibitor) would be altered with extended passage. Given that gene expression results indicated some models undergo profound changes with in vivo passage, a general metric of stability was generated so models could be ranked accordingly. Lastly, changes occurring during transition from in vitro to in vivo growth may have important consequences for therapeutic studies since targets identified in vitro could be over- or under-represented when tumor cells adapt to in vivo growth. A comprehensive list of mouse transcripts capable of cross-hybridizing with human probe sets on the HG-U133 Plus 2.0 array was generated. Removal of the murine artifacts followed by pairwise analysis of in vitro cells with respective passage 1 xenografts and GO analysis illustrates the complex interplay that each model has with the host microenvironment.

Conclusions

This study provides strategies to aid selection of xenograft models for therapeutic studies. These data highlight the dynamic nature of xenograft models and emphasize the importance of maintaining passage consistency throughout experiments.

【 授权许可】

   
2014 Hollingshead et al.; licensee BioMed Central Ltd.

【 图 表 】

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