Accelerated Progression of Asbestos-Induced Mesotheliomas in Heterozygous p53+/- Mice

Abstract

Asbestos fibers produce diffuse malignant mesotheliomas in chronic rodent inhalation assays or after direct intrapleural or intraperitoneal injection. In vitro models have provided evidence that asbestos fibers are genotoxic carcinogens that can directly or indirectly generate reactive oxygen- and nitrogen-derived species that cause DNA damage. Heterozygous p53+/- mice show an increased incidence and reduced latency of malignant mesotheliomas induced by weekly intraperitoneal injections of crocidolite asbestos fibers. In this study, we investigated whether loss of heterozygosity (LOH) at the p53 tumor-suppressor gene locus contributes to accelerated tumor progression. LOH was found in 50% of the tumors produced in heterozygous p53+/- mice. In contrast to tumors that arise in p53+/+ mice or those that retained one p53 allele, LOH was associated with large tumor masses with central areas of necrosis, local invasion, and penetration of lymphatics. Increased tumor size was not associated with increased levels of cell proliferation as determined by BrdU incorporation, but it was correlated with a reduction in apoptosis as determined morphologically and by the TUNEL assay. Wild-type p53 protein is essential for cell cycle arrest in response to DNA damage and in maintenance of genomic stability. Cell lines established from tumors that showed LOH at the p53 tumor-suppressor gene locus were nearly tetraploid. These results suggest that p53 haplo-insufficiency sensitizes mice to the clastogenic or aneuploidogenic effects of crocidolite asbestos fibers, resulting in a shorter latent period. As solid tumors develop, spontaneous loss of the wild-type allele accompanied by decreased apoptosis and genetic instability is associated with accelerated tumor growth, invasion, and lymphatic dissemination.

Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube

“…When asbestos was applied intraperitoneally to this model, mesotheliomas were induced with short latency as well (Marsella et al,1997;Vaslet et al,2002). Here, although the genotoxic effect of MWCNT is unclear, our results suggested that intraperitoneal administration of MWCNT possesses carcinogenic potential in p53(+/−) mice presumably depending on its size/shape and persistency in the organism.…”

“…Deduced from those factors, we hypothesized that MWCNT might have carcinogenic potency similar to asbestos when administered to organisms via the same route of exposure. Here, we adopted a short-term bioassay, i.e., the p53 heterozygous mouse intraperitoneal exposure model reported to be sensitive to asbestos and develop mesotheliomas fast (Marsella et al, 1997;Vaslet et al, 2002). This mouse model has been reported to be sensitive not only to genotoxic carcinogens (Pritchard et al, 2003) but also to reactive oxygen species (ROS)-related carcinogenesis (Tazawa et al, 2007) and therefore fits with the postulated carcinogenesis mechanisms of asbestos and asbestos-like particles (Marsella et al, 1997;Vaslet et al, 2002).…”

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…This further emphasises the differences between radiation-induced apoptosis and that resulting from a carcinogen. Although tumour suppression by p53 is tissue type-dependent, a decrease in dosage of the p53 gene has been shown to promote carcinogen-induced tumorigenesis at many sites, 34,35 including skin, 36 bladder, 37 lung, 38 salivary gland 39 and oesophagus. 40 These studies have shown that p53 is important in controlling early events in oncogenesis in these tissues, but it has not been clear until now that this also applied to colon.…”

A Mouse Model Recapitulating Molecular Features of Human Mesothelioma

“…Genomic DNA was isolated from primary murine malignant mesothelioma cell cultures, and exons 4 to 11 of the Tp53 gene were PCR amplified using Platinum Taq DNA Polymerase High Fidelity (Invitrogen, Carlsbad, CA), as previously described (14). The products were cloned into a pCRII-Topo vector (Invitrogen) and sequenced using Tp53 intron-specific forward and reverse primers.…”