ferric-oxide--saccharated and Mesothelioma

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.

Topics: Adsorption; Animals; Asbestos; Asbestosis; Benzoates; Carcinogens, Environmental; Carcinoma, Renal Cell; Cell Transformation, Neoplastic; Comparative Genomic Hybridization; Deferasirox; Ferric Compounds; Ferric Oxide, Saccharated; Genes, p16; Glucaric Acid; Humans; Iron Chelating Agents; Iron Overload; Japan; Kidney Neoplasms; Male; Mesothelioma; Mineral Fibers; Peritoneal Neoplasms; Phlebotomy; Pleural Neoplasms; Rats; Triazoles

Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2'-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers, Tumor; Calbindin 2; Cell Cycle Proteins; Cell Line, Tumor; Chromosome Deletion; Deoxyguanosine; Down-Regulation; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Iron; Iron Overload; Lung Neoplasms; Male; Membrane Glycoproteins; Mesothelioma; Mesothelioma, Malignant; Neoplasms, Experimental; Nuclear Proteins; Rats; Rats, Wistar; RNA Splicing Factors; Thromboxane-A Synthase

In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2'-deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

Topics: Animals; Comparative Genomic Hybridization; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Female; Ferric Compounds; Ferric Oxide, Saccharated; Gene Deletion; Gene Expression Profiling; Genes, p16; Glucaric Acid; Hematinics; Male; Mesoderm; Mesothelioma; Mucoproteins; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Peritoneal Neoplasms; Rats; Rats, Inbred F344; Rats, Wistar; Transcription Factors; Uromodulin