Differential Transcriptomic Analysis of Spontaneous Lung Tumors in B6C3F1 Mice: Comparison to Human Non–Small Cell Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related death in people and is mainly due to environmental factors such as smoking and radon. The National Toxicology Program (NTP) tests various chemicals and mixtures for their carcinogenic hazard potential. In the NTP chronic bioassay using B6C3F1 mice, the incidence of lung tumors in treated and control animals is second only to the liver tumors. In order to study the molecular mechanisms of chemically induced lung tumors, an understanding of the genetic changes that occur in spontaneous lung (SL) tumors from untreated control animals is needed. The authors have evaluated the differential transcriptomic changes within SL tumors compared to normal lungs from untreated age-matched animals. Within SL tumors, several canonical pathways associated with cancer (eukaryotic initiation factor 2 signaling, RhoA signaling, PTEN signaling, and mammalian target of rapamycin signaling), metabolism (Inositol phosphate metabolism, mitochondrial dysfunction, and purine and pyramidine metabolism), and immune responses (FcγR-mediated phagocytosis, clathrin-mediated endocytosis, interleukin 8 signaling, and CXCR4 signaling) were altered. Meta-analysis of murine SL tumors and human non–small cell lung cancer transcriptomic data sets revealed a high concordance. These data provide important information on the differential transcriptomic changes in murine SL tumors that will be critical to our understanding of chemically induced lung tumors and will aid in hazard analysis in the NTP 2-year carcinogenicity bioassays.

Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice

“…Data processing and identification of differentially expressed genes was done as previously described (Hoenerhoff et al 2011; Pandiri et al 2012) Briefly, array fluorescent pixel intensity measurements were acquired and gene expression data were normalized across all samples using the robust multiarray analysis (RMA) methodology (Irizarry et al 2003). Using RMA-normalized data, for each probe set, pairwise comparisons (AN vs. HB and AN vs. HCC) were made using a bootstrap t-test while controlling the mixed directional false discovery rate (FDR) (Guo et al 2010).…”

21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision‐Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial‐Induced Lung Fibrosis

“…Previously published, publicly available gene expression microarray data from mouse lungs exposed to a variety of stressors that are known to cause lung disease (i.e., lung inflammation, emphysema, chronic obstructive pulmonary disease [COPD], lung fibrosis, and lung cancer) were used. [19][20][21][22][23][24][25][26][27][28][29][30] The PFS17 was pre-validated using transcriptomics data generated in-house from mice exposed to multi-walled carbon nanotubes (MWCNTs) that are suspected to induce fibrosis in mouse lungs. Furthermore, an ex vivo precision-cut lung slice (PCLS) technique, an alternative to whole animal testing, was optimized for the assessment of lung fibrosis using bleomycin as a model pro-fibrotic agent and was tested for its applicability to assess ENMs-induced lung fibrosis for the HHRA purpose.…”

Comparative Pathobiology of Environmentally Induced Lung Cancers in Humans and Rodents

“…Interestingly, the pulmonary adenocarcinomas in smokers and chemically induced bronchioloalveolar carcinomas in mice usually harbor G to T transversions (Husgafvel-Pursiainen and Kannio, 1996, Hong et al , 2007, Hong et al , 2008, Riely et al , 2008, Sills et al , 1999). Meta-analysis of transcriptomic alterations in human and mouse lung tumors revealed significant similarities in lung cancer pathways in both species (Stearman et al , 2005, Bonner et al , 2004, Pandiri et al , 2012). These data indicate that mouse lung tumors are similar to human adenocarcinomas at the morphologic and molecular levels and that mouse lung tumors are relevant in evaluating carcinogenic hazards associated with environmental exposures.…”