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ABSTRACT: Inorganic arsenic in the drinking water is a multi-site human carcinogen that potentially targets the kidney. Recent evidence also indicates developmental arsenic exposure impacts renal carcinogenesis in humans and mice. Emerging theory indicates that cancer may be a disease of stem cells (SCs), and 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 bi-weekly 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 loss of contact inhibition, and increased invasiveness, both cancer cell characteristics. Compared to 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 non-adherent spheroid bodies that grew much more aggressively in Matrigel, typical of cancer SCs (CSCs). The transformed cells also showed gene over-expression typical of renal SCs/CSCs (CD24, Osr1, Ncam) and arsenic adaptation such as over-expression of Mt-1, Mt2, Sod-1, and Abcc2. These data suggest inorganic arsenic induced an acquired cancer phenotype in vitro in these rat kidney SCs potentially forming CSCs and, consistent with data in vivo, indicate these multipotent SCs may be targets of arsenic during renal carcinogenesis.
Chemical Research in Toxicology 11/2012; · 3.78 Impact Factor
