Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats.
The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.
['Okazaki|Yasumasa|Y|https://orcid.org/0000-0003-1054-9403', 'Misawa|Nobuaki|N|', 'Akatsuka|Shinya|S|', 'Kohyama|Norihiko|N|', 'Sekido|Yoshitaka|Y|', 'Takahashi|Takashi|T|', 'Toyokuni|Shinya|S|https://orcid.org/0000-0002-5757-1109']
D000818:Animals D001194:Asbestos D017636:Asbestos, Amphibole D017638:Asbestos, Crocidolite D017632:Asbestos, Serpentine D055028:Comparative Genomic Hybridization D050762:Cyclin-Dependent Kinase Inhibitor p15 D019941:Cyclin-Dependent Kinase Inhibitor p16 D006720:Homozygote D006801:Humans D008175:Lung Neoplasms D008654:Mesothelioma D000086002:Mesothelioma, Malignant D051381:Rats D012307:Risk Factors D017384:Sequence Deletion
Cdkn2a/2b malignant mesothelioma anthophyllite tremolite animal model