Reply to “Reversal and Prevention of Arsenic-Induced Human Bronchial Epithelial Cell Malignant Transformation by MicroRNA-200b”

Toxicological Sciences, Aug 2011

Samuel M. Cohen

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Reply to “Reversal and Prevention of Arsenic-Induced Human Bronchial Epithelial Cell Malignant Transformation by MicroRNA-200b”

Samuel M. Cohen [email protected] 0 0 Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE 68198-3135 - In reviewing the article by Wang et al. entitled, Reversal and Prevention of Arsenic-Induced Human Bronchial Epithelial Cell Malignant Transformation by MicroRNA-200b, I became concerned regarding the pathology of the tumors that grew in the nude mice upon transplantation of bronchial epithelial cells transformed by arsenite in vitro. The documentation of the pathology consists of a single, small photograph which is difficult to interpret with regard to the histopathology. Based on appearance, however, I am concerned that these tumors do not represent bronchial epithelial malignancies, but rather, either represent inflammatory tissue or mesenchymal proliferation, either benign or malignant. Whether inflammation or mesenchymal proliferation, neither would be indicative of an effect that is representative of the kinds of tumors that occur in humans in response to arsenic. The authors indicate that there is epithelial to mesenchymal transformation in vitro, and they take this as a sign of malignant transformation. However, in reality, that is a late effect in malignant progression and usually is associated with metastatic growth for lung tumors. The tumors in humans that are induced by arsenic are all carcinomas. Lung carcinomas in humans rarely have sarcomatoid (mesenchymal) differentiation, which represent a rare subtype, and even in those tumors epithelial differentiation is evident. More substantial evidence should be provided by the authors that these truly represent epithelial-derived tumors, either additional histopathology or more definitively by a pankeratin immunohistochemical stain. Without such documentation, the interpretation of this article is misleading. If these are not carcinomas, the publication would be more accurate to indicate that they have produced epithelial to mesenchymal transformation but that this does not necessarily imply carcinoma transformation in vitro by arsenite. For comparison, in vitro transformation of urothelial cells by trivalent arsenicals produced carcinomas when transplanted into nude mice (Somji et al., 2006; Wnek et al., 2010). A more limited issue that also needs to be addressed is that this transformation in vitro is only occurring in p53-deficient cells. This is similar to other in vitro models with arsenic, such as those involving urothelial UROTsa cells that have been reported by others (Somji et al., 2006; Wnek et al., 2010). In contrast, individuals who develop tumors in response to arsenic exposure are usually not p53 deficient nor are many of the tumors that are induced. Somji, S., Zhou, X. D., Garrett, S. H., Sens, M. A., and Sens, D. A. (2006). Urothelial cells malignantly transformed by exposure to cadmium (Cd(2)) and arsenite (As(3)) have increased resistance to Cd(2) and As(3)induced cell death. Toxicol. Sci. 94, 293301. Wnek, S. M., Jensen, T. J., Severson, P. L., Futscher, B. W., and Gandolfi, A. J. (2010). Monomethylarsonous acid produces irreversible events resulting in malignant transformation of a human bladder cell line following 12 weeks of low-level exposure. Toxicol. Sci. 116, 4457. (...truncated)


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Samuel M. Cohen. Reply to “Reversal and Prevention of Arsenic-Induced Human Bronchial Epithelial Cell Malignant Transformation by MicroRNA-200b”, Toxicological Sciences, 2011, pp. 606-606, 122/2, DOI: 10.1093/toxsci/kfr128