title: 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.
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.
authors.affiliation: Biological Testing Branch, National Cancer Institute at Frederick, 1050 Boyles Street, Building 1043, Room 11, Frederick, MD 21702, USA. hollingm@mail.nih.gov.
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Hollingshead
authors.forename: Luke H
authors.initials: LH
authors.lastname: Stockwin
authors.forename: Sergio Y
authors.initials: SY
authors.lastname: Alcoser
authors.forename: Dianne L
authors.initials: DL
authors.lastname: Newton
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Orsburn
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Bonomi
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Borgel
authors.forename: Raymond
authors.initials: R
authors.lastname: Divelbiss
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Dougherty
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hager
authors.forename: Susan L
authors.initials: SL
authors.lastname: Holbeck
authors.forename: Gurmeet
authors.initials: G
authors.lastname: Kaur
authors.forename: David J
authors.initials: DJ
authors.lastname: Kimmel
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kunkel
authors.forename: Angelena
authors.initials: A
authors.lastname: Millione
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mullendore
authors.forename: Howard
authors.initials: H
authors.lastname: Stotler
authors.forename: Jerry
authors.initials: J
authors.lastname: Collins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020794:Receptor Protein-Tyrosine Kinases; D017239:Paclitaxel; D002945:Cisplatin