Molecular pathogenesis of malignant mesothelioma

Abstract

Malignant mesothelioma (MM) is an aggressive tumor arising primarily from the pleural or peritoneal cavities. It develops by asbestos exposure after a long latency, which is characterized by insidious growth and clinical presentation at an advanced stage of disease. MM is highly refractory to conventional therapies even with a combination of aggressive surgical intervention and multimodality strategies, with cure remaining elusive. Molecular genetic analysis has revealed several key genetic alterations, which are responsible for the development and progression of MM. The cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF), neurofibromatosis type 2 (NF2) and BRCA1-associated protein-1 (BAP1) genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM. Merlin, which is encoded by NF2, regulates multiple cell signaling cascades including the Hippo and mammalian target of rapamycin pathways, which regulate cell proliferation and growth. BAP1 is involved in histone modification and its inactivation induces the disturbance of global gene expression profiling. The discovery of a new familial cancer syndrome with germline mutation of BAP1 also indicates the importance of genetic factors in MM susceptibility. Meanwhile, although frequent expression and functional activations of oncogene products such as receptor tyrosine kinases are observed in MM cells, activating mutations of these genes are rare. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them will be applied for developing new diagnostic tools and new target therapies against MMs.

Asbestos-Related Research: First Objectivity then Conclusions

“…Chrysotile may undergo not only longitudinal splitting but also breakage into shorter fibers, which may be cleared more readily [18]; however, short chrysotile fibers were reported to prevail in the pleura [48,52]. The paradigm of fiber migration to the pleura agrees with the primary affect of asbestos-related Mt usually occurring in the parietal rather than visceral pleura [54].…”

Second line therapy in malignant pleural mesothelioma: A systematic review

“…MPM is particularly characterized by the loss of tumor suppressor genes, rather than gain of function mutations. The most frequently mutated tumor suppressor genes are discussed here and their possible implications for therapeutic interventions [26].…”

“…Together with Focal Adhesion Kinase (FAK) it also inhibits the growth of cancer stem cells. Other key pathways are the mammalian target of rapamycin (mTOR); the Hippo pathway, which is important in cell proliferation, and extracellular signal-regulated kinase (ERK) pathways [26,27]. mTOR activity is up regulated in the absence of merlin, leading to increased cell proliferation.…”

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival

“…It arises from the surface serosal cells of the pleura and peritoneum and in rare instances, the pericardium or gonads [1]. Exposure to asbestos fibers is the most common cause of MM.…”

“…Genetic analysis reveals involvement of a number of different signaling pathways and several important genetic alterations [1], which includes RAS-MEK-ERK, PI3K-AKT, m-TOR, Merlin, Hippo and angiogenesis pathways, interference in cell cycle and epigenetic changes. These mechanisms were described in detail in recent review articles [1] [4]- [7].…”