The Genes-Stemness-Secretome Interplay in Malignant Pleural Mesothelioma: Molecular Dynamics and Clinical Hints

Abstract

MPM has a uniquely poor somatic mutational landscape, mainly driven by environmental selective pressure. This feature has dramatically limited the development of effective treatment. However, genomic events are known to be associated with MPM progression, and specific genetic signatures emerge from the exceptional crosstalk between neoplastic cells and matrix components, among which one main area of focus is hypoxia. Here we discuss the novel therapeutic strategies focused on the exploitation of MPM genetic asset and its interconnection with the surrounding hypoxic microenvironment as well as transcript products and microvesicles representing both an insight into the pathogenesis and promising actionable targets.

Keywords: genetics; malignant pleural mesothelioma; microenvironment; targeted therapies.

Figure 1

Immunohistochemistry workup in case of pleural masses and suspect of MPM. The study should include the expression of vimentin 8, TTF1, p40, calretinin, WT-1, D240, citokeratin 5/6, vimentin, S100, BER-EP4, CEA, CD31, CD34, desmin, and myogenin D1. The most relevant differential diagnosis regards MPM (e.g., calretinin positive) vs. pleural metastases from lung cancer (e.g., PAS-positive staining in case of adenocarcinoma -ADC); in some cases, results might not solve the origin of neoplastic cells proliferating into the pleural space. Moreover, differential diagnosis requires the exclusion of undifferentiated MPM, the presence of a small/dormant lung primary carcinoma, a pleural localization of melanoma (expression of S100), rhabdomyosarcoma (expression of desmin and myogenin D1), and angiosarcoma (expression of CD31, CD34), ectopic lung epithelial cells which undergo a malignant transformation, or of epithelial cancer from an unknown primary site of origin. **= possible, * = rare.