Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis

Abstract

Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated because of the long incubation period for MM.

Malignant mesothelioma as an oxidative stress-induced cancer: An update

“…p16 INK4a /p14 ARF deletion was also detected in rat peritoneal mesotheliomas established by repeated injection with iron saccharate and an iron chelator, NTA [72]. As iron is crucially involved in both models, the similarity between fiber and ironinduced carcinogenesis again highlights the significance of iron overload and oxidative stress in the underlying genomic alterations that occur so frequently in these malignancies [62,73].…”

Epidemiology of malignant peritoneal mesothelioma: A population-based study

“…More than one fourth of the cases were diagnosed microscopically only during autopsy indicating that the diagnostics of MPeM are quite demanding due to the disease's long latency period and obscure symptoms [8,16]. In addition our results indicate that more than half of the MPeM cases had spread beyond the regional lymph nodes at the time of diagnosis.…”

Dual preventive benefits of iron elimination by desferal in asbestos‐induced mesothelial carcinogenesis

“…(6) Irrespective of the types of asbestos, postadministration of nitrilotriacetate (NTA; iron chelating agent to promote the Fenton reaction) (11,12) significantly shortened the periods of carcinogenesis, confirming the major role of iron in this process. (13,14) In the case of chrysotile, which does not include iron in itself, its hemolytic activity and the subsequent adsorption of hemoglobin were important, (15) in addition to the general affinity of asbestos to histones. (16) We also reported that i.p.…”