title: Efficient Transformation of Primary Human Mesenchymal Stromal Cells by Adenovirus Early Region 1 Oncogenes.
abstract: Previous observations that human amniotic fluid cells (AFC) can be transformed by human adenovirus type 5 (HAdV-5) E1A/E1B oncogenes prompted us to identify the target cells in the AFC population that are susceptible to transformation. Our results demonstrate that one cell type corresponding to mesenchymal stem/stroma cells (hMSCs) can be reproducibly transformed by HAdV-5 E1A/E1B oncogenes as efficiently as primary rodent cultures. HAdV-5 E1-transformed hMSCs exhibit all properties commonly associated with a high grade of oncogenic transformation, including enhanced cell proliferation, anchorage-independent growth, increased growth rate, and high telomerase activity as well as numerical and structural chromosomal aberrations. These data confirm previous work showing that HAdV preferentially transforms cells of mesenchymal origin in rodents. More importantly, they demonstrate for the first time that human cells with stem cell characteristics can be completely transformed by HAdV oncogenes in tissue culture with high efficiency. Our findings strongly support the hypothesis that undifferentiated progenitor cells or cells with stem cell-like properties are highly susceptible targets for HAdV-mediated cell transformation and suggest that virus-associated tumors in humans may originate, at least in part, from infections of these cell types. We expect that primary hMSCs will replace the primary rodent cultures in HAdV viral transformation studies and are confident that these investigations will continue to uncover general principles of viral oncogenesis that can be extended to human DNA tumor viruses as well.
  
  
  OBJECTIVE
  It is generally believed that transformation of primary human cells with HAdV-5 E1 oncogenes is very inefficient. However, a few cell lines have been successfully transformed with HAdV-5 E1A and E1B, indicating that there is a certain cell type which is susceptible to HAdV-mediated transformation. Interestingly, all those cell lines have been derived from human embryonic tissue, albeit the exact cell type is not known yet. We show for the first time the successful transformation of primary human mesenchymal stromal cells (hMSCs) by HAdV-5 E1A and E1B. Further, we show upon HAdV-5 E1A and E1B expression that these primary progenitor cells exhibit features of tumor cells and can no longer be differentiated into the adipogenic, chondrogenic, or osteogenic lineage. Hence, primary hMSCs represent a robust and novel model system to elucidate the underlying molecular mechanisms of adenovirus-mediated transformation of multipotent human progenitor cells.
authors: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors: Thomas
authors: T
authors: Speiseder
authors: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors: Helga
authors: H
authors: Hofmann-Sieber
authors: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors: Estefanía
authors: E
authors: Rodríguez
authors: Department of Oncology, Hematology, BMT with Section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Anna
authors: A
authors: Schellenberg
authors: Department of Oncology, Hematology, BMT with Section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Nuray
authors: N
authors: Akyüz
authors: Department of Oncology, Hematology, BMT with Section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Judith
authors: J
authors: Dierlamm
authors: Institute of Medical Microbiology, University of Regensburg, Regensburg, Germany.
authors: Thilo
authors: T
authors: Spruss
authors: Research Department Cell and Gene Therapy, Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Claudia
authors: C
authors: Lange
authors: Heinrich Pette Institute-Leibniz Institute for Experimental Virology, Hamburg, Germany thomas.dobner@hpi.uni-hamburg.de.
authors: Thomas
authors: T
authors: Dobner
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000235:genetics* / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002869:Chromosome Aberrations; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D059785:Karyotype; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000473:pathology / Q000821:virology*; D009857:Oncogenes; D061251:Primary Cell Culture; D051381:Rats; D014162:Transfection
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins
keywords: DNA tumor viruses; E1A; E1B; hMSCs; host-virus interactions; human tumor viruses; viral transformation and carcinogenesis