Document Detail


Suitability of animal models for studying radiation-induced thyroid cancer in humans: evidence from nuclear architecture.
MedLine Citation:
PMID:  22136268     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Rat and mouse have been widely used to estimate the radiation risk and tumorigenic effects of radiation with extrapolating the findings to humans. RET/PTC is a characteristic genetic alteration frequently found in radiation-induced thyroid cancer in human populations. Recently, nuclear architecture and spatial proximity between recombinogenic genes have been implicated as important factors in the generation of RET/PTC and other chromosomal rearrangements in human cells. However, it is unknown whether the nuclear architecture in rodent thyroid cells is similar to that of human thyroid cells. The aim of this study was to test whether the proximity effects that are observed between loci involved in RET/PTC rearrangements in humans are conserved across different species.
METHODS: Using 3D fixation, fluorescence in situ hybridization, and confocal microscopy, we compared the distance between genes involved in RET/PTC rearrangement in normal thyroid cells from humans, mice, and rats.
RESULTS: While in humans, RET, NCOA4, and H4 are all located on the same chromosome (10q), in rodents these genes are located on separate chromosomes. In mouse, RET is located on chromosome 6F1, NCOA4 on 14B, and H4 on 10B5.3. In rat, RET is on chromosome 4q42, NCOA4 on 16p16, and H4 (TST1) on 9q36. We further observed that in human thyroid cells, mean distance between genes involved in two most common types of RET/PTC, that is, RET and NCOA4 (partners of RET/PTC3) and RET and H4 (partners of RET/PTC1), was 1.08±0.04 and 1.24±0.05 μm, respectively. In mouse thyroid cells, these distances were 3.21±0.1 and 3.43±0.1 μm, and in rat cells the values were 3.37±0.1 and 3.87±0.1 μm (p<0.001). Moreover, we found that in contrast to human thyroid cells, in rodent cells these genes were randomly positioned with respect to each other.
CONCLUSIONS: The differences in nuclear architecture and spatial positioning of genes involved in RET/PTC rearrangements between human and rodent thyroid cells raise a concern about suitability of animal models for assessing RET/PTC-driven thyroid carcinogenesis in humans.
Authors:
Manoj Gandhi; Yuri E Nikiforov
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Thyroid : official journal of the American Thyroid Association     Volume:  21     ISSN:  1557-9077     ISO Abbreviation:  Thyroid     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-05     Completed Date:  2012-04-03     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9104317     Medline TA:  Thyroid     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1331-7     Citation Subset:  IM    
Affiliation:
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Nucleus / pathology*
Cytoskeletal Proteins / genetics
Disease Models, Animal
Gene Rearrangement*
Humans
In Situ Hybridization, Fluorescence
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Neoplasms, Radiation-Induced / genetics*,  pathology
Nuclear Receptor Coactivators / genetics
Proto-Oncogene Proteins c-ret / genetics
Rats
Rats, Sprague-Dawley
Reproducibility of Results
Species Specificity
Thyroid Gland / pathology*
Thyroid Neoplasms / etiology,  genetics*,  pathology
Grant Support
ID/Acronym/Agency:
CA88041/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/CCDC6 protein, human; 0/Cytoskeletal Proteins; 0/NCOA4 protein, human; 0/NcoA4 protein, mouse; 0/Nuclear Receptor Coactivators; EC 2.7.10.1/Proto-Oncogene Proteins c-ret; EC 2.7.10.1/RET protein, human; EC 2.7.10.1/Ret protein, mouse
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