Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. However, the late stage of MPM diagnosis and the long latency that exists between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. In this review, we discuss the current molecular and genetic contributors in MPM pathogenesis and the risk factors associated with these carcinogenic processes.

French cohort of the uranium processing workers: mortality pattern after 30-year follow-up

“…Although recent epidemiological reviews (Baas et al 1998;Teta et al 2007;Yang et al 2008) provide strong evidence for a causal association between radiation exposure and risk of malignant pleural mesothelioma, this evidence is mostly based on high radiation doses received for therapeutic purposes rather on occupational radiation exposure (Hill et al 1997;Huncharek 2002;Kawashima et al 1990;Lerman et al 1991;Shannon et al 1995;Weiner and Neragi-Miandoab 2008;Weissmann et al 1996). Studies of nuclear workers where association between pleural cancer mortality and radiation exposure was tested, found no association with internal radiation (McGeoghegan and Binks 2000), or with external radiation exposure (Telle-Lamberton et al 2007).…”

Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma

“…The EGFR is a transmembrane tyrosine kinase receptor that plays an important role in many tumorigenic processes, including cell growth, proliferation, invasion, and metastasis. These effects are mediated by activation of downstream signaling pathways, including RAS-RAF-mitogen-activated protein kinase and phosphatidylinositol-3 kinase (PI3K)-AKT pathways [1,2]. Mutations in the tyrosine kinase (TK) domain of the EGFR gene are present in a subset of non-small cell lung cancers (NSCLCs), and those tumors with EGFR mutations have been reported to be highly sensitive to EGFR TK inhibitors [3].…”

“…It is frequently associated with asbestos exposure and characterized by altered DNA methylation patterns [1,2]. One of the most frequent genetic alterations found in mesothelioma is the homozygous deletion of INK4a/ARF locus (in more than 70% of the cases) that contributes to two tumor suppressor cellular pathways, the ARF/p53 and the INK4a/RB [1]. Since these two pathways are considered to be the main regulators of cellular senescence, it is reasonable consider mesothelioma a failure of the senescence response [3].…”

Mesothelioma: an update

“…Nearly 95% of the asbestos used worldwide is chrysotile and most others fibres are commonly used with chrysotile. Other risk factors have been incriminated [8]. A high level of evidence is associated with environmental exposure to erionite or fluoro-edenite and for irradiation [9] while controversial data supported the role of man-made ceramic fibres or viral contamination by simian virus 40 (SV40).…”