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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
- Source :
- BMC Genomics
- Publisher :
- Springer Nature
-
Abstract
- 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. Electronic supplementary material The online version of this article (doi: 10.1186/1471-2164-15-393) contains supplementary material, which is available to authorized users.
- Subjects :
- Transcriptomic stability
Paclitaxel
Transplantation, Heterologous
Mice, Nude
Antineoplastic Agents
Biology
Bioinformatics
Transcriptomic expression
Mice
Xenograft models
In vivo
Serial passage
Cell Line, Tumor
Neoplasms
Genetics
Animals
Cluster Analysis
Humans
NCI-60 cell line screen
Affymetrix HG-U133 Plus 2.0 array
Oligonucleotide Array Sequence Analysis
Regulation of gene expression
cDNA microarray
Microarray analysis techniques
Gene Expression Profiling
Receptor Protein-Tyrosine Kinases
Receptors, Prostaglandin E, EP2 Subtype
Xenograft Model Antitumor Assays
In vitro
Transplantation
Gene expression profiling
Mice, Inbred C57BL
Gene Expression Regulation
Drug Resistance, Neoplasm
Cancer research
Female
in vitro to in vivo transition
DNA microarray
Cisplatin
Research Article
Biotechnology
Subjects
Details
- Language :
- English
- ISSN :
- 14712164
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- BMC Genomics
- Accession number :
- edsair.doi.dedup.....7a08fc5739951ddc77a6dc03029384c9
- Full Text :
- https://doi.org/10.1186/1471-2164-15-393