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

Hoenerhoff, Mark J.; Hong, Hue Hua L.; Ton, Tai Vu; Lahousse, Stephanie A.; Sills, Robert C.

doi:10.1177/0192623309351726

Cited by 51 publications

(32 citation statements)

References 137 publications

(272 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In that respect, it is interesting that toxicological studies have shown that the carcinogen o-nitrotoluene, used to synthesize agricultural and rubber products, induces both cecal carcinomas and mesotheliomas in rodent models, possibly through perturbation of the Wnt/b-catenin pathway. 38,39 In summary, our analyses demonstrate that structural alterations involving chr16p13.2 occur frequently in both adenomas and carcinomas. Our data furthermore indicate that the presence of a chr16p13.2 alteration identifies a subgroup of patients with aggressive tumors and poor clinical outcome.…”

Section: Discussionmentioning

confidence: 59%

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Andersen

Lamy

Thorsen

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n 5 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p 5 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.Despite major efforts over the recent years toward improving the survival outcome of patients with colorectal cancer (CRC), the disease remains a major health burden with over one million cases worldwide and a disease-specific mortality of $33% in the developed world. 1 Currently, the gold standard for prognostication is clinicopathological staging, based on the Tumor, Node, Metastasis (TNM) classifcation. However. Although CRC is often diagnosed at a stage where complete resection of the primary cancer (Stages I-III) is possible, 40-50% of patients who undergo potentially curative surgery alone relapse and die of metastatic disease. 2 Although most patients with Stage III (lymph-node positive) cancer receive adjuvant treatment, it is offered to only a subset of Stage II (localized disease) patients presenting with specific high-risk clinical features, including tumor perforation or invasion of adjacent organs. 3 This approach is clearly suboptimal, resulting in undertreatment of $20% of Stage II patients who will recur. Similarly, current adjuvant treatment is clearly ineffective in many Stage III patients, with a recurrence rate of $40% 4,5 highlighting the need for treatment with more aggressive or newly emerging targeted therapies, e.g., inhibitors of epidermal growth factor recepto...

show abstract

Section: Discussionmentioning

confidence: 59%

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Andersen

Lamy

Thorsen

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Identification of early stage biomarkers of NGCs has been previously studied to aid the identification of molecules with carcinogenic potential 3 . Potential biomarkers include increased relative liver weight, hepatocyte labelling index 4 , hepatocellular necrosis, hypertrophy and cytomegally in short term toxicity studies in both rats and mice 5 .…”

Section: Introductionmentioning

confidence: 99%

A Metabolomics Investigation of Non-genotoxic Carcinogenicity in the Rat

et al. 2013

View full text Add to dashboard Cite

Non-genotoxic carcinogens (NGCs) promote tumour growth by altering gene expression which ultimately leads to cancer without directly causing a change in DNA sequence. As a result NGCs are not detected in mutagenesis assays. Whilst there are proposed biomarkers of carcinogenic potential, the definitive identification of non-genotoxic carcinogens still rests with the rat and mouse long term bioassay. Such assays are expensive, time consuming, require a large number of animals and their relevance to human health risk assessments is debatable. Metabolomics and lipidomics in combination with pathology and clinical chemistry were used to profile perturbations produced by 10 compounds which represented a range of rat non-genotoxic hepatocarcinogens (NGC), non-genotoxic non-hepatocarcinogens (non-NGC) and a genotoxic hepatocarcinogen. Each compound was administered at its maximum tolerated dose level for 7, 28 and 91 days to male Fisher 344 rats. Changes in liver metabolite concentration differentiated the treated groups across different time points. The most significant differences were driven by pharmacological mode of action, specifically by the peroxisome proliferator activated receptor alpha (PPAR-α) agonists. Despite these dominant effects, good predictions could be made when differentiating NGCs from non-NGCs. Predictive ability measured by leave one out cross validation was 87% and 77% after 28 days of dosing for NGCs and non-NGCs, respectively. Amongst the discriminatory metabolites we identified free fatty acids, phospholipids, triacylglycerols, as well as precursors of eicosanoid and the products of reactive oxygen species linked to processes of inflammation, proliferation and oxidative stress. Thus, metabolic profiling is able to identify changes due to the pharmacological mode of action of xenobiotics and contribute to early screening for non-genotoxic potential.

show abstract

“…Rodent models lend further support that they were of potential human health risk. Rat had similar response to inflammation and infection as human [10]. In order to establish an animal model for eye research, we used rat eye and the chemical FA to examine corneal injury.…”

Section: Nigella Sativa Groupmentioning

confidence: 99%

Role of Nigella sativa seed oil on corneal injury induced by formaldehyde in adult male albino rats

et al. 2016

View full text Add to dashboard Cite

show abstract

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

Cited by 51 publications

References 137 publications

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

A Metabolomics Investigation of Non-genotoxic Carcinogenicity in the Rat

Role of Nigella sativa seed oil on corneal injury induced by formaldehyde in adult male albino rats

Contact Info

Product

Resources

About