A Review of the Molecular Mechanisms of Chemically Induced Neoplasia in Rat and Mouse Models in National Toxicology Program Bioassays and Their Relevance to Human Cancer

Cellular and Molecular Pathology Branch, National Institutes of Environmental Health Sciences, Research Triangle Park, NC 27519, USA.
Toxicologic Pathology (Impact Factor: 2.14). 10/2009; 37(7):835-48. DOI: 10.1177/0192623309351726
Source: PubMed


Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, the authors examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. National Toxicology Program (NTP) studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds.

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    • "Previous studies reported more significant MALAT1 lncRNA overexpression in NSCLC compared with that in other cancers22 and that lncRNA is a possible regulatory factor of metastasis.23 Given these previous findings, we aimed to determine whether the same would hold true for other lncRNAs in pulmonary adenocarcinoma, which has been described as the most prevalent form of NSCLC.33 "
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    ABSTRACT: Background The purpose of this study was to investigate differentially expressed long noncoding RNAs (lncRNAs) in pulmonary adenocarcinoma tissue and adjacent noncancerous tissue from Chinese patients using lncRNA expression microarray and preliminary analysis. Methods RNA extracted from three paired pulmonary adenocarcinoma tissue and adjacent noncancerous tissue specimens was used to synthesize double-stranded complementary DNA after labeling and hybridization. The complementary DNA was labeled and hybridized to the lncRNA expression microarray, and array data were analyzed for hierarchical clustering. Gene coexpression networks were constructed to identify interactions among genes. To validate the microarray findings, we measured the relative expression levels of four random differentially expressed lncRNAs in the same tissue used for microarray using real-time quantitative polymerase chain reaction. The expression level of one lncRNA, AK124939, in the paired pulmonary adenocarcinoma/adjacent noncancerous tissue of another 30 patients was measured using real-time quantitative polymerase chain reaction. The experimental data were further analyzed and compared with clinical features. Results Of 39,000 lncRNAs investigated, 704 were differentially expressed in pulmonary adenocarcinoma tissue; 385 were upregulated and 319 were downregulated compared with those in the adjacent noncancerous tissue (fold change ≥2 and ≤−2, P<0.05). AK124939 expression levels in poorly differentiated adenocarcinoma tissue were lower than those found in well to moderately differentiated adenocarcinoma tissue (P=0.05). Conclusion There are significant differences in the lncRNA expression profiles in Chinese patients with pulmonary adenocarcinoma. LncRNAs such as AK124939 may be anticancer factors related to the progression of pulmonary adenocarcinoma.
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    • "''Uncertain findings.'' Not only were these increased forestomach tumor incidences very weak as a function of dose (1/50, 0/50, 1/ 50, 5/50 in control, low, middle and high doses, respectively), but the forestomach is not considered to be an appropriate organ for cancer hazard assessment since humans do not even have this organ (Cohen and Arnold, 2011; Hoenerhoff et al., 2009 "
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    • "The relevance of rodent carcinogenesis for humans has been discussed in numerous publications (Maronpot, Flake, and Huff 2004; Anisimov, Ukraintseva, and Yashin 2005; Hoenerhoff et al. 2009). Although relevance has been demonstrated in some cases but not in others, animal models remain important in predicting human risk for carcinogens (Huff 2010). "
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