New Perspectives on Diagnosis and Therapy of Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare, but severe form of cancer, with an incidence that varies significantly within and among different countries around the world. It develops in about one to two persons per million of the general population, leading to thousands of deaths every year worldwide. To date, the MPM is mostly associated with occupational asbestos exposure. Asbestos represents the predominant etiological factor, with approximately 70% of cases of MPM with well-documented occupational exposure to asbestos, with the exposure time, on average greater than 40 years. Environmental exposure to asbestos is increasingly becoming recognized as a cause of mesothelioma, together with gene mutations. The possible roles of other cofactors, such as viral infection and radiation exposure, are still debated. MPM is a fatal tumor. This cancer arises during its early phase without clinical signs. Consequently, its diagnosis occurs at advanced stages. Standard clinical therapeutic approaches include surgery, chemo- and radiotherapies. Preclinical and clinical researches are making great strides in the field of this deadly disease, identifying new biomarkers and innovative therapeutic approaches. Among the newly identified markers and potential therapeutic targets, circulating microRNAs and the Notch pathway represent promising avenues that could result in the early detection of the tumor and novel therapeutic approaches.

Keywords: Notch; asbestos; biomarker; gene; malignant pleural mesothelioma; microRNA; simian virus 40; therapy.

Figure 1

Potential therapeutic targets and biomarkers in the mesothelioma. Asbestos fibers, alone or with other cofactors, such as viral infection or genetic predisposition, may cause mutagenic changes resulting in the alterations of oncogenes and tumor suppressor genes leading to the transformation of normal mesothelial cells. In addition, following necrosis caused by asbestos exposure, HMGB1 primarily located in the nucleus, translocates to the cytosol and extracellular space, triggering the inflammatory response and TNF-α secretion, both by mesothelial cells and macrophages, further contributing to mesothelial cells transformation. All these events may contribute to the activation of the Notch signaling. Targeting Notch, as it is already been pursued with VEGFR and EGFR, could help to stop the progression of mesothelioma. Mesothelioma is also accompanied by changes in microRNA (miRNA) expression in cancer cells and, consequently, in biological fluids. In particular, miRNAs (miR-197-3p, miR-1281, and miR-32-3p) could become a tool for early diagnosis of mesothelioma. In this figure, the red and green arrows represent clinical and preclinical studies, respectively, aimed to sensitize mesothelioma cells to cytotoxic treatments by targeting newly discovered pathways altered in mesothelioma. The purple arrow indicates the novel potential circulating biomarkers under study for a no invasive MPM screening. Abbreviations: VEGFR, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor; HMGB1, high-mobility group box-1; TNF-α, tumor necrosis factor-α; MPM, malignant pleural mesothelioma.