American Medical Journal 3 (2): 240-248, 2012 ISSN 1949-0070 © 2012 Science Publications Corresponding Author: Arti Shukla, Department Pathology 216 HSRF, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT Tel: 802-656-8253 Fax: 802-656-8892 240 The Role of Inflammation in Development and Therapy of Malignant Mesothelioma Jill Miller and Arti Shukla Department Pathology, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT Abstract: Malignant Mesothelioma (MM) is an asbestos related malignancy with a poor prognosis and limited therapeutic approaches. The pathogenesis of MM has been linked to asbestos induced inflammation. Asbestos exposure results in reactive oxygen species generation, infiltration of inflammatory cells and prolonged release of multiple cytokines, oxidants and growth factors. The role of inflammation in MM has led to the evaluation of inflammatory profiles as prognostic and therapeutic markers. Additionally, inflammatory pathways are under investigation for potential therapeutic interventions. In this review, we discuss the role of inflammation in MM pathogenesis, inflammatory markers with potential clinical impact for MM and clinical trials that target inflammatory pathways and responses for treatment of MM. Ultimately, MM remains a difficult to treat cancer that requires multimodality therapy. Key words: Best Investigator’s Choice, Malignant Mesothelioma (MM), Reactive Oxygen Species, Malignant Pleural Mesothelioma, Extrapleural Pneumonectomy INTRODUCTION Malignant Mesothelioma (MM) is caused by asbestos and produces devastating tumor types with poor prognosis and no effective therapeutic approaches. Asbestos exposure is known to increase the risk of pulmonary pathology in the form of nonmalignant inflammatory diseases, such as pleural plaques, pleural effusions and asbestosis and malignant diseases such as mesothelioma and bronchogenic carcinoma. The differences in the cellular phenotype involved (alveolar, epithelial, or mesothelial cells) defines the outcome of disease. Asbestos-induced inflammatory changes may, in part, be responsible for diseases. Pleural plaque is produced by the effect of recurrent inflammatory and repair processes occurring for long time periods. Chronic inflammatory episodes may predispose to malignant evolution, as it is known that the majority of MM develops on pleura affected by pleural plaques and not on the normal pleura. A survey of the current literature suggests that there is more than one mechanism involved in the pathogenesis of asbestos- induced mesothelioma. One proposed mechanism is the oxidative stress concept that highlights how iron within asbestos fibers catalyzes free radical generation and thereby induces oxidative stress and carcinogenesis (Shukla et al., 2003). Another proposed mechanism is the chronic inflammatory theory that is founded on the observation that inflammation is a biologic response to pathogenic materials and injured cells in which various types of cells, such as neutrophils, macrophages, fibroblasts and vascular endothelial cells, interact with each other. Over time, inflammation becomes chronic and plays an important role in asbestos-induced carcinogenesis that is characterized by persistent release of cytokines and oxidants from macrophages. One way proinflammatory cytokines promote carcinogenesis in epithelial and mesothelial cells is by altering signaling pathways and thereby inhibiting apoptosis. In addition, persistent macrophage activation plays important roles in initiation, as well as promotion, of pathological processes in mesothelioma. The remaining mechanisms include the chromosome tangling concept, which postulates that asbestos fibers damage chromosomes when cells divide and the adsorption concept which states that the surface of asbestos possesses a high affinity for certain molecules including components of cigarette smoke as well as endogenous molecules. In the present review, we focus on the role of inflammation in development and therapy of MM. Asbestos exposure related inflammatory changes leading to malignant mesothelioma: Asbestos exposure to cells and tissues results in Reactive Oxygen Species (ROS) generation that triggers lipid peroxidation, leading to inflammation related gene