Kuroda Akio
Unit of Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi Hiroshima, Hiroshima, 739-8530, Japan.
Genes Environ. 2021 Oct 12;43(1):46. doi: 10.1186/s41021-021-00215-0.
Most cases of mesothelioma are known to result from exposure to asbestos fibers in the environment or occupational ambient air. The following questions regarding asbestos toxicity remain partially unanswered: (i) why asbestos entering the alveoli during respiration exerts toxicity in the pleura; and (ii) how asbestos causes mesothelioma, even though human mesothelial cells are easily killed upon exposure to asbestos. As for the latter question, it is now thought that the frustrated phagocytosis of asbestos fibers by macrophages prolongs inflammatory responses and gives rise to a "mutagenic microenvironment" around mesothelial cells, resulting in their malignant transformation. Based on epidemiological and genetic studies, a carcinogenic model has been proposed in which BRCA1-associated protein 1 mutations are able to suppress cell death in mesothelial cells and increase genomic instability in the mutagenic microenvironment. This leads to additional mutations, such as CDKN2A [p16], NF2, TP53, LATS2, and SETD2, which are associated with mesothelioma carcinogenesis. Regarding the former question, the receptors involved in the intracellular uptake of asbestos and the mechanism of transfer of inhaled asbestos from the alveoli to the pleura are yet to be elucidated. Further studies using live-cell imaging techniques will be critical to fully understanding the mechanisms underlying asbestos toxicity.
已知大多数间皮瘤病例是由于在环境或职业环境空气中接触石棉纤维所致。以下关于石棉毒性的问题仍部分未得到解答：（i）为什么呼吸过程中进入肺泡的石棉会在胸膜中产生毒性；以及（ii）尽管人类间皮细胞在接触石棉后很容易被杀死，但石棉是如何导致间皮瘤的。至于后一个问题，现在认为巨噬细胞对石棉纤维的吞噬受挫会延长炎症反应，并在间皮细胞周围产生“诱变微环境”，导致它们发生恶性转化。基于流行病学和遗传学研究，已经提出了一种致癌模型，其中BRCA1相关蛋白1突变能够抑制间皮细胞的细胞死亡，并增加诱变微环境中的基因组不稳定性。这会导致额外的突变，如CDKN2A [p16]、NF2、TP53、LATS2和SETD2，这些与间皮瘤的致癌作用有关。关于前一个问题，参与石棉细胞内摄取的受体以及吸入的石棉从肺泡转移到胸膜的机制尚待阐明。使用活细胞成像技术进行进一步研究对于充分理解石棉毒性的潜在机制至关重要。
