title: Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors.
abstract: BACKGROUND
  Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established--namely, the Swarm Rat Chondrosarcoma (SRC)--and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy.
  
  
  METHODS
  To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC.
  
  
  RESULTS
  The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression.
  
  
  CONCLUSIONS
  This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that thymosin-β4 may have a role in chondrosarcoma metastasis.
authors.affiliation: Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hamm
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Stevens
authors.forename: Hehuang
authors.initials: H
authors.lastname: Xie
authors.forename: Elio F
authors.initials: EF
authors.lastname: Vanin
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morcuende
authors.forename: Hakeem
authors.initials: H
authors.lastname: Abdulkawy
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.forename: Simone T
authors.initials: ST
authors.lastname: Sredni
authors.forename: Jared M
authors.initials: JM
authors.lastname: Bischof
authors.forename: Deli
authors.initials: D
authors.lastname: Wang
authors.forename: Sergey
authors.initials: S
authors.lastname: Malchenko
authors.forename: Maria de Fatima
authors.initials: Mde F
authors.lastname: Bonaldo
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Casavant
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D002813:Chondrosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D016762:Genes, fos / Q000502:physiology; D006801:Humans; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms / Q000209:etiology* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013947:Thymosin / Q000235:genetics / Q000378:metabolism; D013977:Tibia / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D000099201:Thymosin beta(4)
chemical_list: D014408:Biomarkers, Tumor; D055513:Connective Tissue Growth Factor; D013947:Thymosin; D000099201:Thymosin beta(4); C526316:CCN2 protein, rat
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