title: Chronic exposure of renal stem cells to inorganic arsenic induces a cancer phenotype.
abstract: Inorganic arsenic in the drinking water is a multisite human carcinogen that potentially targets the kidney. Recent evidence also indicates that developmental arsenic exposure impacts renal carcinogenesis in humans and mice. Emerging theory indicates that cancer may be a disease of stem cells (SCs) and that there are abundant active SCs during early life. Therefore, we hypothesized that inorganic arsenic targets SCs, or partially differentiated progenitor cells (PCs), for oncogenic transformation. Thus, a rat kidney SC/PC cell line, RIMM-18, was chronically exposed to low-level arsenite (500 nM) for up to 28 weeks. Multiple markers of acquired cancer phenotype were assessed biweekly during arsenic exposure, including secreted matrix metalloproteinase (MMP) activity, proliferation rate, colony formation in soft agar, and cellular invasiveness. Arsenic exposure by 10 weeks and after also induced marked and sustained increases in colony formation, indicative of the loss of contact inhibition, and increased invasiveness, both cancer cell characteristics. Compared to the passage-matched control, chronic arsenic exposure caused exposure-duration dependent increases in secreted MMP-2 and MMP-9 activity, Cox-2 expression, and more rapid proliferation (all >2-fold), characteristics typical of cancer cells. Dysregulation of SC maintenance genes and signaling pathways are common during oncogenesis. During arsenite exposure, expression of several genes associated with normal kidney development and SC regulation and differentiation (i.e., Wt-1, Wnt-4, Bmp-7, etc.) were aberrantly altered. Arsenic-exposed renal SCs produced more nonadherent spheroid bodies that grew much more aggressively in Matrigel, typical of cancer SCs (CSCs). The transformed cells also showed gene overexpression typical of renal SCs/CSCs (CD24, Osr1, Ncam) and arsenic adaptation such as overexpression of Mt-1, Mt2, Sod-1, and Abcc2. These data suggest that inorganic arsenic induced an acquired cancer phenotype in vitro in these rat kidney SCs potentially forming CSCs and, consistent with data in vivo, indicate that these multipotent SCs may be targets of arsenic during renal carcinogenesis.
authors.affiliation: National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Person
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Alan O
authors.initials: AO
authors.lastname: Perantoni
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001151:Arsenic / Q000633:toxicity*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D001151:Arsenic; D051927:CD24 Antigen; D051546:Cyclooxygenase 2; D006023:Glycoproteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008668:Metallothionein; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010455:Peptides; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000715087:ABCC2 protein, human; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat