Pathological and molecular biological approaches to early mesothelioma

Abstract

Malignant mesothelioma is an asbestos-related malignancy that arises primarily from mesothelial cells on the serosal surfaces of the pleural, peritoneal, and pericardial cavities. Malignant pleural mesothelioma (MPM) is most common, and its incidence is dramatically increasing worldwide as a result of widespread use of asbestos. Morphological discrimination between MPM and reactive mesothelial hyperplasia is difficult, and the most reliable pathological criterion for malignancy is mesothelial proliferation invading deeply into subpleural adipose tissues. To establish radical cure of MPM, it is crucial to find early-stage MPM of epithelial type, in which mesothelial proliferation is localized on the serosal surface of parietal pleura or limited within the submesothelial fibrous tissues of parietal pleura. The initial clinical presentation for patients with MPM is frequently dyspnea and/or chest pain due to large pleural effusion, and cytological analysis of pleural effusions is valuable to find patients with early-stage MPM of epithelial type. Recently, cytological features of MPM in pleural effusion, molecular markers for MPM, and genetic alternations of MPM have been reported. In this review, we discuss major issues on pathological and molecular biological approaches for diagnosis of early-stage MPM of epithelial type.

Gene Expression of Mesothelioma in Vinylidene Chloride–exposed F344/N Rats Reveal Immune Dysfunction, Tissue Damage, and Inflammation Pathways

“…By comparing gene expression of mesotheliomas in VDC-exposed animals to spontaneous mesotheliomas, the non-specific oncogenic background cancer effects are normalized, and chemical effects in the context of oncogenesis can be more easily interpreted. Gene expression profiling and mutation analysis of human mesotheliomas has revealed a variety of genetic alterations including mutations in tumor suppressor genes ( TP53, P16, BAP1, WT1, NF2, PTEN ) and cell cycle genes ( CDKN2A/2B and CDKN2C ), and alterations in proteins associated with tumorigenesis (COL3, CCL2, LGALS) (Bueno et al 2010; Gordon et al 2005; Gueugnon et al 2011; Tsujimura et al 2012). In large part, similarities between spontaneous mesotheliomas and those from vinylidene chloride-exposed animals primarily involved genes associated with tumorigenesis.…”

The established and future biomarkers of malignant pleural mesothelioma

“…Several gene expression profiling studies have determined a plethora of upregulated and downregulated genes and regions of chromosomal losses and gains, but most studies have analyzed gene expression in tumor versus normal tissue [97][98][99][100][101][102][103][104][105][106][107][108][109]. Among the important differentially over-expressed genes and pathways are anti-apoptotic genes, angiogenesis, metabolic regulating genes, several DNA repair gene pathways, cell adhesion, chemokines, detoxification genes, chemo-, radio-and multidrug resistant genes, oncogenes and generally genes driving all phases of cell cycle [97][98][99]101,104,110].…”

Immunological Risks Caused by Fibrous and Particulate Substances

“…As shown in Figure 1, the most important and critical complications that arise in asbestosexposed patients concern the development of malignancies, such as lung cancer and MM [25][26][27][28][29]. Of course, asbestos fibers possess carcinogenic-related activities, such as oxygen stress caused by iron in the asbestos fibers, frustrated macrophages incapable of phagocytosing asbestos fibers, chromosome tangling, and the absorption of other carcinogenic substances inhaled in the lung, such as materials from tobacco smoke and other air pollutants [34][35][36]. However, given the long latency period that precedes the onset of MM following initial exposure to asbestos, it was considered that asbestos fibers cause alterations in antitumor immunity by recurrent and chronic encounters with various immune cells at the lung and related lymph nodes.…”

“…Given the conflict that has arisen due to economic considerations and the medical evidence, there is a confusion concerning the pathological mechanisms of asbestos-induced cancers, and in particular, an uncertainty concerning the dangers of iron-absent chrysotile (white) asbestos compared with iron-present crocidolite (blue) and amosite (brown) asbestos [30][31][32][33]. However, regarding the poor prognosis of MM, novel medical approaches to investigate the biological effects of asbestos and pathological mechanisms of asbestos-induced carcinogenesis, as well as clinical trials to detect early stages of MM, should be implemented to assist in the development of improved prevention strategies and cure of asbestos-related malignancies [34][35][36]. From this standpoint, our group has been investigating the immunological effects of asbestos with respect to the reduction of tumor immunity [11,12,15,16].…”