恶性间皮瘤(MM)的发作与暴露于石棉纤维有关。石棉纤维被分类为蛇纹石(温石棉)或闪石,其中包括青石棉,amosite,直闪石,透闪石,和阳起石类型。虽然很少有研究,已证明直闪石与间皮瘤有关,和透闪石,滑石和温石棉中的污染物,是致癌的危险因素。这里,在通过扫描电子显微镜表征这些纤维的长度和宽度之后,我们探索了透闪石和直闪石在永生化人间存细胞系(MeT5A)细胞中诱导的细胞毒性,鼠巨噬细胞(RAW264.7),在大鼠模型中。透闪石和短的直闪石纤维被吞噬并定位为空泡,而长的直闪石纤维被捕获在MeT5A和Raw264.7细胞的伪足上,根据透射电子显微镜。一项为期2天的延时研究结果表明,透闪石被吞噬并破坏了MeT5A和RAW264.7细胞,但是直闪石对这些细胞没有细胞毒性。腹腔注射透闪石致大鼠弥漫性浆膜增厚,而直叶石在腹膜浆膜表面形成局灶性纤维化和肉芽肿。此外,Cdkn2a/2b的损失,这是人类MM中最经常丢失的病灶,通过基于阵列的比较基因组杂交技术在8例大鼠MM中观察到(纯合缺失[5/8]和杂合性缺失[3/8])。这些结果表明透闪石可引发间皮损伤并持续抑制吞噬细胞,导致随后的腹膜纤维化和MM。讨论了基于纤维直径/长度的致癌性的可能机理。
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.