Histological sequence of the development of rat mesothelioma by MWCNT, with the involvement of apolipoproteins

A rat model of mesothelioma development by peritoneal injection of multiwalled carbon nanotube (MWCNT) has been established and found to be useful to understand the mechanisms underlying fibrous particles-associated carcinogenesis. Its detailed histological sequence, however, remains largely obscure. We thus aimed to assess the time-course of mesothelioma development by MWCNT, and evaluate a set of lipoprotein-related molecules as potential mechanism-based biomarkers for the phenomenon. Male Fischer 344 rats were intraperitoneally injected with MWCNT (MWNT-7) at 1 mg/kg body weight, and necropsied at 8, 16, 24, 32, and 42 weeks after injection. For biochemical analyses of the lipoprotein-related molecules, more samples, including severe mesothelioma cases, were obtained from 2 other carcinogenicity tests. Histologically, in association with chronic inflammation, mesothelial proliferative lesions appeared around week 24. Before and at the beginning of the tumor development, the prominent infiltration of CD163-positive cells was seen in the vicinity of mesothelial cells. The histological pattern of early mesothelioma was not a papillary structure, but rather a characteristic structure with a spherical appearance, composed of the mesothelioma cells in the surface area, which were underlain by connective tissue-like cells. Along with the progression, mesotheliomas started to exhibit versatile histological subtypes. Serum levels of apolipoprotein A-I and -IV, and a ratio of HDL-cholesterol to total-cholesterol were inversely correlated with mesothelioma severity. Altogether, the detailed histological sequence of mesotheliomagenesis by MWCNT is demonstrated, and it is indicated that the altered profile of apolipoproteins may be involved in its underlying mechanisms.