Decoding the Molecular Enigma Behind Asbestos and Fibrous Nanomaterial-induced carcinogenesis.

Abstract

Objectives: Natural fibrous mineral, asbestos, has been useful in industry for many centuries. In the 1960's, epidemiology had recognized the association between asbestos exposure and mesothelioma and the IARC designated all kinds of asbestos as Group 1 in 1987. However, various scientific enigmas remained regarding the molecular mechanisms of asbestos-induced mesothelial carcinogenesis. This review article was undertaken to reveal and summarize the recent discoveries how the enigma has been resolved.

Methods: We collected recent important findings of our own laboratory and the others to explain why mesothelial cells are the target for asbestos-induced carcinogenesis and what is the key molecular mechanisms.

Results: Long incubation period of 30 ~ 40 years for mesothelial carcinogenesis after asbestos exposure is responsible for the asbestos fibers to go through the pulmonary parenchyma from the central to peripheral portions finally to reach the parietal mesothelium by piercing visceral pleura. Asbestos fibers have affinity for hemoglobin and histones, thus accumulating iron on the surface while travelling through the lung. The other important point is that mesothelial cells are phagocytic cells, engulfing iron-coated asbestos fibers. Accordingly, homozygous deletion of 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 in multiwalled carbon nanotube of ~50-nm-diameter.

Conclusion: Physical dimension, biopersistence and affinity to iron/histones are essential for fibrous material to be carcinogenic to mesothelial cells. Therefore, local iron reduction maybe a strategy to prevent mesothelial carcinogenesis.