title: Arsenic exposure transforms human epithelial stem/progenitor cells into a cancer stem-like phenotype.
abstract: BACKGROUND
  Inorganic arsenic is a ubiquitous environmental carcinogen affecting millions of people worldwide. Evolving theory predicts that normal stem cells (NSCs) are transformed into cancer stem cells (CSCs) that then drive oncogenesis. In humans, arsenic is carcinogenic in the urogenital system (UGS), including the bladder and potentially the prostate, whereas in mice arsenic induces multi-organ UGS cancers, indicating that UGS NSCs may represent targets for carcino-genic initiation. However, proof of emergence of CSCs induced by arsenic in a stem cell population is not available.
  
  
  METHODS
  We continuously exposed the human prostate epithelial stem/progenitor cell line WPE-stem to an environmentally relevant level of arsenic (5 microM) in vitro and determined the acquired cancer phenotype.
  
  
  RESULTS
  WPE-stem cells rapidly acquired a malignant CSC-like phenotype by 18 weeks of exposure, becoming highly invasive, losing contact inhibition, and hyper-secreting matrix metalloproteinase-9. When hetero-transplanted, these cells (designated As-CSC) formed highly pleomorphic, aggressive tumors with immature epithelial- and mesenchymal-like cells, suggesting a highly pluripotent cell of origin. Consistent with tumor-derived CSCs, As-CSCs formed abundant free-floating spheres enriched in CSC-like cells, as confirmed by molecular analysis and the fact that only these floating cells formed xeno-graft tumors. An early loss of NSC self-renewal gene expression (p63, ABCG2, BMI-1, SHH, OCT-4, NOTCH-1) during arsenite exposure was sub-sequently reversed as the tumor suppressor gene PTEN was progressively suppressed and the CSC-like phenotype acquired.
  
  
  CONCLUSIONS
  Arsenite transforms prostate epithelial stem/progenitor cells into CSC-like cells, indicating that it can produce CSCs from a model NSC population.
authors.affiliation: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Bhalchandra A
authors.initials: BA
authors.lastname: Diwan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010641:Phenotype; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D018874:Spheroids, Cellular / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D018053:Arsenites; C081876:CKAP4 protein, human; D002274:Carcinogens, Environmental; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020780:Matrix Metalloproteinase 9; C015001:arsenite; D001151:Arsenic