title: Chronic cadmium exposure in vitro causes acquisition of multiple tumor cell characteristics in human pancreatic epithelial cells.
abstract: BACKGROUND
  Cancer may be a stem cell (SC)-based disease involving formation of cancer SCs (CSCs) potentially arising from transformation of normal SCs. Cadmium has been linked to human pancreatic cancer.
  
  
  OBJECTIVE
  We studied cadmium exposure of human pancreatic ductal epithelial (HPDE) cells and whether SCs may be targeted in this process.
  
  
  METHODS
  We chronically exposed HPDE cells to low level cadmium (1 μM) for ≤ 29 weeks. Nonadherent spheroid formation was used to indicate CSC-like cell production, and we assessed tumor cell characteristics in such spheres. Assessed tumor cell characteristics including secretion of matrix metalloproteinase-9 (MMP-9), invasion, and colony formation were fortified by evaluating expression of relevant genes by real-time reverse transcription polymerase chain reaction and by Western blot.
  
  
  RESULTS
  Increased MMP-9 secretion and overexpression of the pancreatic cancer marker S100P occurred in chronic (29 weeks of exposure) cadmium-exposed (CCE) cells. CCE cells also showed markedly higher colony formation and invasion, typical of cancer cells. Floating "spheres" of viable cells, known to contain an abundance of normal SCs or CSCs, form in vitro with many cell types. CCE cells produced 3-fold more spheres than control cells and were more invasive, secreted more MMP-9, and overexpressed markers for pancreatic SCs/CSCs (i.e., CXCR4, OCT4, CD44) and S100P, a marker for pancreatic cancer. CCE-derived spheres rapidly produced aggressive, highly branched, and poorly differentiated glandular-like structures in Matrigel.
  
  
  CONCLUSIONS
  Chronic cadmium exposure produced multiple tumor cell characteristics in HPDE cells and CCE cell-derived spheres. These data support the plausibility of cadmium as a human pancreatic carcinogen.
authors.affiliation: Inorganic Toxicology Group, 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: Wei
authors.initials: W
authors.lastname: Qu
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kim
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Bell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004785:Environmental Pollutants / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000139:chemically induced*; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D002104:Cadmium