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Toxicol Pathol. 2014 Jul;42(5):863-76. doi: 10.1177/0192623313501894. Epub 2013 Aug 26.

Spontaneous mesotheliomas in F344/N rats are characterized by dysregulation of cellular growth and immune function pathways.

Author information

1
Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina, USA.
2
Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina, USA.
3
Cellular and Molecular Pathology Branch, Division of the National Toxicologic Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
4
Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
5
Microarray Core, Toxicology and Pharmacology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
6
Cellular and Molecular Pathology Branch, Division of the National Toxicologic Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA hoenerhm@niehs.nih.gov.

Abstract

Aged male Fischer 344/N rats are prone to developing spontaneous peritoneal mesotheliomas that arise predominantly from the tunica vaginalis of the testes. A definitive cause for the predominance of this neoplasm in F344/N rats is unknown. Investigation of the molecular alterations that occur in spontaneous rat mesotheliomas may provide insight into their pathogenesis as well enable a better understanding regarding the mechanisms underlying chemically induced mesothelioma in rodents. Mesothelial cell function represents a complex interplay of pathways related to host defense mechanisms and maintenance of cellular homeostasis. Global gene expression profiles of spontaneous mesotheliomas from vehicle control male F344/N rats from 2-year National Toxicology Program carcinogenicity bioassays were analyzed to determine the molecular features of these tumors and elucidate tumor-specific gene expression profiles. The resulting gene expression pattern showed that spontaneous mesotheliomas are associated with upregulation of various growth factors, oncogenes, cytokines, pattern recognition response receptors, and pathogen-associated molecular patterns receptors, and the production of reactive oxygen and nitrogen species, as well as downregulation of apoptosis pathways. Alterations in these pathways in turn trigger molecular responses that stimulate cell proliferation and promote tumor survival and progression.

KEYWORDS:

F344/N rat; Fred-PE cells; National Toxicology Program; gene expression; mesothelial cell; mesothelioma; microarray

PMID:
23980201
PMCID:
PMC4967937
DOI:
10.1177/0192623313501894
[Indexed for MEDLINE]
Free PMC Article
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