title: Recruitment of normal stem cells to an oncogenic phenotype by noncontiguous carcinogen-transformed epithelia depends on the transforming carcinogen.
abstract: BACKGROUND
  Cancer stem cells (CSCs) drive tumor initiation, progression, and metastasis. The microenvironment is critical to the fate of CSCs. We have found that a normal stem cell (NSC) line from human prostate (WPE-stem) is recruited into CSC-like cells by nearby, but noncontiguous, arsenic-transformed isogenic malignant epithelial cells (MECs).
  
  
  OBJECTIVE
  It is unknown whether this recruitment of NSCs into CSCs by noncontact co-culture is specific to arsenic-transformed MECs. Thus, we used co-culture to examine the effects of neighboring noncontiguous cadmium-transformed MECs (Cd-MECs) and N-methyl-N-nitrosourea-transformed MECs (MNU-MECs) on NSCs.
  
  
  RESULTS
  After 2 weeks of noncontact Cd-MEC co-culture, NSCs showed elevated metalloproteinase-9 (MMP-9) and MMP-2 secretion, increased invasiveness, increased colony formation, decreased PTEN expression, and formation of aggressive, highly branched duct-like structures from single cells in Matrigel, all characteristics typical of cancer cells. These oncogenic characteristics did not occur in NSCs co-cultured with MNU-MECs. The NSCs co-cultured with Cd-MECs retained self-renewal capacity, as evidenced by multiple passages (> 3) of structures formed in Matrigel. Cd-MEC-co-cultured NSCs also showed molecular (increased VIM, SNAIL1, and TWIST1 expression; decreased E-CAD expression) and morphologic evidence of epithelial-to-mesenchymal transition typical for conversion to CSCs. Dysregulated expression of SC-renewal genes, including ABCG2, OCT-4, and WNT-3, also occurred in NSCs during oncogenic transformation induced by noncontact co-culture with Cd-MECs.
  
  
  CONCLUSIONS
  These data indicate that Cd-MECs can recruit nearby NSCs into a CSC-like phenotype, but MNU-MECs do not. Thus, the recruitment of NSCs into CSCs by nearby MECs is dependent on the carcinogen originally used to malignantly transform the MECs.
authors.affiliation: National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Person
authors.forename: Ruben G
authors.initials: RG
authors.lastname: Orihuela
authors.forename: Ntube N O
authors.initials: NN
authors.lastname: Ngalame
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004785:Environmental Pollutants / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004785:Environmental Pollutants; D016211:Transforming Growth Factor alpha; D002104:Cadmium; D008770:Methylnitrosourea; D020782:Matrix Metalloproteinases