Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma

Abstract

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 0 -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.

Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

“…Concerning mesothelioma, iron overload as a major pathogenic process has been recently studied (3,19,20). We reported that intraperitoneal injection of iron saccharate into rats induced mesothelioma (21) with loss of the Cdkn2a/2b tumor suppressor gene, the same genetic feature as asbestos-induced mesothelioma, supporting the hypothesis that iron overload is responsible for asbestos-induced mesothelial carcinogenesis (22). More recently, we showed that administration of nitrilotriacetate, an iron chelator to enhance catalytic activity of iron, significantly reduced the period of asbestos-induced mesothelial carcinogenesis in rats not only by crocidolite or amosite but also by chrysotile (20).…”

“…All rats used were Fischer 344/Brown Norway F1 hybrids, which do not generate spontaneous mesothelioma (20,22). Fischer 344 female rats and Brown Norway male rats were purchased from Charles River Laboratories.…”

Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis: Shedding light on fiber entry mechanism

“…As a consequence of DNA damage in mesothelial cells, homozygous deletion of the Cdkn2a/2b tumor suppressor genes is frequently observed, not only in asbestos-induced mesothelioma (21,22) but also in carbon nanotube-induced mesothelioma. (17) We previously showed that mesothelioma induced by iron saccharate also displayed homozygous deletion of Cdkn2a/2b, (23) suggesting that the loss of these genes might be a major event in mesothelial carcinogenesis.…”

Endometriosis-Associated Ovarian Cancer: The Role of Oxidative Stress

“…Alternatively, the high concentration of free iron in endometrial cysts may directly provide oxidative stress that induces genomic mutation in epithelial cells (Yamaguchi, 2008), and whether the direct pathway or the indirect pathway involving macrophages has a major role in carcinogenesis remains to be resolved. Iron overload in experimental animals enhances epithelial cell proliferation (Defrere, 2006) and causes malignant tumors with genomic abnormalities (Hu, 2010), which suggests a similar mechanism leading to carcinogenesis in human endometriosis (Fig. 1).…”