Toyokuni Shinya, Kong Yingyi
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.
J Occup Health. 2025 Jan 7;67(1). doi: 10.1093/joccuh/uiae064.
The natural fibrous mineral, asbestos, has been useful in industry for many centuries. In the 1960s, epidemiology recognized the association between asbestos exposure and mesothelioma, and in 1987 the International Agency for Research on Cancer designated all kinds of asbestos as Group 1 carcinogens. However, various scientific enigmas remained regarding the molecular mechanisms of asbestos-induced mesothelial carcinogenesis. This review article was undertaken to reveal and summarize recent discoveries to resolve those enigmas.
We collected recent important findings from our own laboratory and others to explain why mesothelial cells are the target for asbestos-induced carcinogenesis and what are the key molecular mechanisms.
The long incubation period of 30-40 years for mesothelial carcinogenesis after asbestos exposure allows the asbestos fibers to go through the pulmonary parenchyma from the central to peripheral portions and ultimately reach the parietal mesothelium by piercing visceral pleura. Asbestos fibers have affinity for hemoglobin and histones, thus accumulating iron on the surface while traveling through the lung. Mesothelial cells are phagocytic cells, engulfing iron-coated asbestos fibers. Accordingly, homozygous deletion of the p16INK4a tumor suppressor gene, a signature of excess iron-induced carcinogenesis, is acquired through oxidative DNA damage. Recently, exosome-dependent iron transfer from asbestos-fed macrophages to mesothelial cells was reported. Similar molecular mechanisms are observed with multiwalled carbon nanotubes of ~50-nm diameter.
Physical dimensions, biopersistence, and affinity to iron/histones are essential for fibrous material to be carcinogenic to mesothelial cells. Therefore, local iron reduction may be a strategy to prevent mesothelial carcinogenesis.
天然纤维矿物质石棉在工业中已被使用了许多世纪。20世纪60年代，流行病学确认了石棉暴露与间皮瘤之间的关联，1987年，国际癌症研究机构将各类石棉指定为1类致癌物。然而，关于石棉诱导间皮细胞癌变的分子机制仍存在各种科学谜团。撰写这篇综述文章旨在揭示和总结近期的发现以解决这些谜团。
我们收集了来自我们自己实验室及其他实验室的近期重要发现，以解释为何间皮细胞是石棉诱导癌变的靶细胞以及关键分子机制是什么。
石棉暴露后间皮细胞癌变的潜伏期长达30 - 40年，这使得石棉纤维能够从肺的中央部分穿过肺实质到达外周部分，并最终通过穿透脏层胸膜到达壁层间皮。石棉纤维对血红蛋白和组蛋白具有亲和力，因此在穿过肺部时会在其表面积累铁。间皮细胞是吞噬细胞，会吞噬包裹有铁的石棉纤维。相应地，通过氧化性DNA损伤获得了p16INK4a肿瘤抑制基因的纯合缺失，这是过量铁诱导癌变的一个特征。最近，有报道称存在外泌体依赖的铁从摄取石棉的巨噬细胞向间皮细胞的转移。在直径约50纳米的多壁碳纳米管中也观察到了类似的分子机制。
物理尺寸、生物持久性以及对铁/组蛋白的亲和力对于纤维材料对间皮细胞致癌至关重要。因此，局部减少铁含量可能是预防间皮细胞癌变的一种策略。
