Global gene expression profiling of mesotheliomas from vehicle control and VDC-exposed male F344N rats

A recent two-year NTP cancer bioassay showed a marked increase in the incidence of malignant mesothelioma arising from the tunica vaginalis in male Fischer 344/N rats exposed to Vinylidene chloride (VDC). Aged male F344/N rats are prone to developing spontaneous peritoneal mesotheliomas, which also arise predominantly from the tunica vaginalis of the testes. A definitive mechanism for the observed increased incidence in VDC-exposed rats is unknown. Investigation of the molecular alterations that occur in mesotheliomas from vehicle control and VDC-exposed rats may provide insight into their pathogenesis, as well enable a better understanding regarding the mechanisms underlying chemically induced mesothelioma in rodents. Mesothelial cell function represents a complex interplay of pathways related to host defense mechanisms and maintenance of cellular homeostasis. Global gene expression profiles of spontaneous mesotheliomas from vehicle control male F344/N rats from various two-year National Toxicology Program carcinogenicity bioassays were compared to mesotheliomas from VDC-exposed rats to characterize the molecular features that are present in mesotheliomas from VDC-exposed animals, and to elucidate tumor-specific gene expression profiles. The resulting gene expression pattern showed that mesotheliomas from VDC-exposed animals are genomically very different from spontaneous tumors; while both tumor types are characterized by alterations in gene expression associated with carcinogenic pathways (oncogenes, tumor suppressor genes, growth factors, etc.), mesotheliomas from VDC-exposed animals are associated with increased dysreguation of immune pathways and inflammatory mediators. Alterations in these pathways may suggest a pro-inflammatory and immune dysfunction signature as one mechanism in the observed increased incidence of these tumors in VDC-exposed animals.近期一项为期两年的美国国家毒理学计划（National Toxicology Program, NTP）癌症生物试验显示，暴露于偏氯乙烯（Vinylidene chloride, VDC）的雄性Fischer 344/N大鼠（Fischer 344/N rats）中，源自睾丸鞘膜（tunica vaginalis）的恶性间皮瘤（malignant mesothelioma）发病率显著升高。 老年雄性Fischer 344/N大鼠易自发出现腹膜间皮瘤（spontaneous peritoneal mesotheliomas），此类肿瘤同样主要起源于睾丸鞘膜。目前，偏氯乙烯暴露大鼠肿瘤发病率升高的确切机制尚不明晰。 对溶剂对照组（vehicle control）与偏氯乙烯暴露大鼠的间皮瘤分子改变开展研究，或可阐明其发病机制，同时助力更深入理解啮齿类化学诱导间皮瘤的潜在作用机制。间皮细胞的功能是宿主防御机制与细胞稳态维持相关通路间的复杂相互作用。 本研究将多项为期两年的美国国家毒理学计划致癌性生物试验（carcinogenicity bioassays）中，溶剂对照组雄性Fischer 344/N大鼠的自发性间皮瘤全基因表达谱（global gene expression profiles），与偏氯乙烯暴露大鼠的间皮瘤表达谱进行对比，旨在表征偏氯乙烯暴露动物来源间皮瘤的分子特征，并阐明肿瘤特异性基因表达模式。 结果显示，偏氯乙烯暴露动物的间皮瘤在基因组层面与自发性肿瘤存在显著差异：尽管两类肿瘤均存在与致癌通路相关的基因表达异常，涉及癌基因（oncogenes）、抑癌基因（tumor suppressor genes）、生长因子（growth factors）等，但偏氯乙烯暴露动物的间皮瘤与免疫通路（immune pathways）及炎症介质（inflammatory mediators）的失调程度更高。此类通路的改变或提示，促炎（pro-inflammatory）及免疫功能异常（immune dysfunction）特征是偏氯乙烯暴露大鼠肿瘤发病率升高的潜在机制之一。